WO2023230504A1

WO2023230504A1 - Methods for treating solid tumors using icos x pd-1 bispecific antibodies

Info

Publication number: WO2023230504A1
Application number: PCT/US2023/067395
Authority: WO
Inventors: David LIEBOWITZ; Patricia MCGOVERN; John Desjarlais; Raphael Clynes; Ying Ding
Original assignee: Xencor, Inc.
Priority date: 2022-05-25
Filing date: 2023-05-24
Publication date: 2023-11-30

Abstract

Provided herein, in certain aspects, are methods for the treatment of a solid tumor in a subject in need thereof, comprising administration of an ICOSxPD-1 bispecific antibody to the subject. The invention is exemplified with Xmab23104. Results from clinical phase I are presented.

Description

METHODS FOR TREATING SOLID TUMORS USING ICOS X PD-1 BISPECIFIC ANTIBODIES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/345,652, filed May 25, 2022, and U.S. Provisional Patent Application No. 63/346,183, filed May 26, 2022, the content of each of which is incorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14718-045-228_SEQLISTING.xml”, was created on May 16, 2023 and is 23,508 bytes in size.

1 FIELD

[0003] Provided herein, in certain aspects, are methods for treating a solid tumor in a subject in need thereof, using an ICOSxPD-1 antibody.

2 SUMMARY

[0004] In one aspect, provided herein is a method of treating a solid tumor in a subject in need thereof, wherein the method comprises: administering to the subject a multispecific antibody comprising a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1 (ICOSxPD-1 antibody), wherein: (a) the first antigen binding domain that binds to ICOS comprises: (i) a heavy chain variable (VH) domain comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and (ii) a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and VL CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and (b) the second antigen binding domain that binds to PD-1 comprises: (i) a VH domain comprising a VH CDR1 , a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NON, respectively; and (ii) a VL domain comprising a VL CDR1, a VL CDR2, and VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 , and SEQ ID NO: 12, respectively; and wherein the administering comprises from about 0.002 mg/kg to about 30 mg/kg of the ICOSxPD-1 antibody, thereby treating the solid tumor.

[0005] In one embodiment, the VH domain of the first antigen binding domain that binds to ICOS comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 13. In one embodiments, the VL domain of the first antigen binding domain that binds to ICOS comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 14. [0006] In one aspect, provided herein is a method of treating a solid tumor in a subject in need thereof, wherein the method comprises: administering to the subject a multispecific antibody comprising a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1 (ICOSxPD-1 antibody), wherein the ICOSxPD-1 antibody comprises: a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 15; a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2- CH3 comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 16; and a third monomer comprising, from N- to C-terminus, a VL-CL comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 17, and wherein the administering comprises from about 0.002 mg/kg to about 30 mg/kg of the ICOSxPD-1 antibody, thereby treating the solid tumor.

[0007] In one embodiment, the scFv comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In one embodiment, the scFv of the first monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8; a VH CDR3 comprising the amino acid sequence of SEQ ID NO:9; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 10; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 11; and/or a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 12. In one embodiment, the VH of the second monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2; and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3. In one embodiment, the VL of the third monomer comprises: a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4; a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6.

[0008] In one embodiment, the solid tumor is refractory, relapsed, or refractory and relapsed solid tumor. In one embodiment, the solid tumor is a newly diagnosed solid tumor. In one embodiment, the solid tumor is selected from the group consisting of undifferentiated pleomorphic sarcoma, non-squamous non-small cell lung carcinoma, soft-tissue sarcoma, myxofibrosarcoma, head and neck squamous cell carcinoma, colorectal cancer, renal cell carcinoma, clear cell histology, melanoma, cervical carcinoma, pancreatic carcinoma, estrogen receptor, progesterone receptor, Her2 negative breast cancer, hepatocellular carcinoma, urothelial carcinoma, nasopharyngeal carcinoma, endometrial carcinoma, small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, and sarcoma. In one embodiment, the solid tumor comprises tumor-infdtrating lymphocytes (TILs) having an elevated ICOS expression level compared to a reference. In one embodiment, the reference is the ICOS expression level obtained from a biological sample comprising lymphocytes obtained from the subject at an earlier time point. In one embodiment, the reference is the ICOS expression level in a biological sample comprising lymphocytes obtained from another subject or a population of subjects diagnosed with the same solid tumor as the subject. In one embodiment, the biological sample is a tumor sample.

[0009] In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.02 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.06 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.2 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.6 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 1.8 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 5.4 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 10 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 15 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 20 mg/kg. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 25 mg/kg. In one embodiment, the TCOSxPD-1 antibody is administered to the subject in an amount of about 30 mg/kg.

[0010] In one embodiment, the method comprises cyclic administration of the ICOSxPD-1 antibody. In one embodiment, each cycle of the cyclic administration is 28 days. In one embodiment, the cyclic administration comprises about or at least about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles, or more than twelve cycles. In one embodiment, the cyclic administration comprises about or at least about 2 cycles of 28 days each. In one embodiment, the ICOSxPD-1 antibody is administered to the subject twice in one cycle. In one embodiment, the ICOSxPD-1 antibody is administered to the subject on Day 1 and 15 of each cycle.

[0011] In one embodiment, the ICOSxPD-1 antibody is administered to the subject once every 2 weeks. In one embodiment, the ICOSxPD-1 antibody is administered to the subject for at least 8 weeks.

[0012] In one embodiment, the administering is via intravenous administration. In one embodiment, the administering is for about 55 to 75 minutes. In one embodiment, the administering is for about or at least about 1 hour. In one embodiment, the ICOSxPD-1 antibody is administered to the subject as a monotherapy.

[0013] Also provided herein is a method of treating a solid tumor in a subject in need thereof, wherein the method comprises: administering to the subject a multispecific ICOSxPD-1 antibody, wherein the method further comprises administering an antibody that binds CTLA-4 (CTLA-4 antibody) to the subject. In one embodiment, the CTLA-4 antibody is ipilimumab. In one embodiment, the CTLA-4 antibody is administered to the subject in an amount of about 1 mg/kg. In one embodiment, the CTLA-4 antibody is administered to the subject a total of 3 times in 2 cycles of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject once every 3 weeks. In one embodiment, the CTLA-4 antibody is administered for at least 8 weeks. In one embodiment, the CTLA-4 antibody is administered to the subject at most about 3 times in 8 weeks. In one embodiment, the CTLA-4 antibody is administered to the subject at most about 4 times in 9 weeks. In one embodiment, the CTLA-4 antibody is administered to the subject at most 4 times. In one embodiment, a first dose of the CTLA-4 antibody is administered to the subject before the start of the first cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject on Day 15 of the first cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject on Day 8 of the second cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject on Day 1 of the third cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject intravenously. In one embodiment, the CTLA-4 antibody is administered to the subject for about 85 minutes to about 105 minutes. In one embodiment, the CTLA-4 antibody is administered to the subject on the same day as the ICOSxPD-1 antibody. In one embodiment, the CTLA-4 antibody is administered to the subject about or at least about 60 minutes before the ICOSxPD-1 antibody. In one embodiment, the first dose of the CTLA-4 antibody is administered to the subject 7 days prior to the first dose of the ICOSxPD-1 antibody. In one embodiment, the ICOSxPD-1 antibody is administered to the subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration; and wherein the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle of the cyclic administration, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of 10 mg/kg on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration; and wherein the CTLA-4 antibody is administered to the subject in an amount of 1 mg/kg, 7 days prior to the start of the first cycle of the cyclic administration, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject between Day 14 and Day 16 of the first cycle of the cyclic administration. In one embodiment, the CTLA-4 antibody is administered to the subject between Day 26 of the second cycle and Day 4 of the third cycle of the cyclic administration. [0014] In one embodiment, the method does not comprise administration of an antibody that binds CTLA-4 (CTLA-4 antibody) to the subject.

[0015] In one embodiment of the methods provided herein, the ICOSxPD-1 antibody is administered to the subject between Day 14 and Day 16 of the first cycle of the cyclic administration. In one embodiment, the ICOSxPD-1 antibody is administered to the subject between Day 26 of the first cycle and Day 4 of the second cycle of the cyclic administration. In one embodiment, the ICOSxPD-1 antibody is administered to the subject between Day 12 and Day 18 of the second cycle, the third cycle, and/or any consecutive cycle of the cyclic administration. In one embodiment, the ICOSxPD-1 antibody is administered to the subject between Day 26 of the second cycle or any subsequent cycle and Day 4 of the third cycle or any subsequent cycle of the cyclic administration.

[0016] In one embodiment, the ICOSxPD-1 antibody is administered to the subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration. In one embodiment, the ICOSxPD- 1 antibody is administered to the subject in an amount of 10 mg/kg on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration.

[0017] In one embodiment, the method further comprises administering an additional agent to the subject. In one embodiment, the additional agent comprises epinephrine, IV fluids, antihistamines, a nonsteroidal anti-inflammatory drug, acetaminophen, a narcotic, oxygen, pressors, and/or a corticosteroid to the subject.

[0018] In one embodiment, the subject is a human subject. In one embodiment, the human subject is 18 years of age or older. In one embodiment, the subject is a treatment-naive subject. In one embodiment, the subject has received previous therapy and has demonstrated disease progression on previous therapy. In one embodiment, the previous therapy comprises treatment with anti-PD-1 monotherapy, platinum-containing combination chemotherapy, anti-cancer therapy, PD-L1 therapy, PD-L2 therapy, or any combination thereof. In one embodiment, the previous therapy comprises treatment with pembrolizumab, carboplatin, pemetrexed, cisplatin, atezolizumab, paclitaxel, bevacizumab, cemiplimab-rwlc, nivolumab, cisplatin-based chemotherapy, carboplatin-based chemotherapy, afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, ceritinib, crizotinib, dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, binimetinib, or any combination thereof. In one embodiment, the previous therapy is pembrolizumab. In one embodiment, the subject is not treated with an anti-PD-1 antibody within 6 weeks before the method.

[0019] In one embodiment, the method results in one or more improved efficacy endpoint in the subject as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Immune- Modified Response Evaluation Criteria in Solid Tumors (imRECIST), and/or modified RECIST 1.1 for immune-based therapeutics (iRECIST) as compared to prior to the method. In one embodiment, the one or more improved efficacy endpoint comprises higher percentage of objective response rate, best overall response, higher percentage of disease control rate, higher percentage of partial response, complete response, longer duration of response, longer progression-free survival, and/or longer overall survival. In one embodiment, the size of the tumor in the subject is reduced after the ICOSxPD-1 antibody is administered to the subject as compared to a reference. In one embodiment, the reference is the size of the tumor prior to the administration of the ICOSxPD-1 antibody to the subject. In one embodiment, the reference is the size of the tumor in another subject or in a population of subjects, wherein the another subject or the population of subjects have the same type and stage of the solid tumor as the subject. In one embodiment, the size of the tumor is reduced by about or at least about 10%, about or at least about 20%, about or at least about 30%, about or at least about 40%, about or at least about 50%, about or at least about 60%, about or at least about 70%, about or at least about 80%, about or at least about 90%, or about 100%. In one embodiment, the one or more improved efficacy endpoint is complete response. In one embodiment, the number of cancer cells in a biological sample obtained from the subject after the ICOSxPD-1 antibody is administered to the subject is lower as compared to a reference.

[0020] In one embodiment, the biological sample is plasma. In one embodiment, the biological sample is blood. In one embodiment, the biological sample is a biopsy from the solid tumor. In one embodiment, the biological sample is serum.

[0021] In one embodiment, the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point. In one embodiment, the reference is a predetermined value. In one embodiment, the reference is the number of cancer cells in a biological sample obtained from a population of subjects with the same type and stage as the solid tumor.

[0022] In specific embodiments of the methods of treatment provided herein, the ICOSxPD- 1 antibody is XmAb®23104. In other specific embodiments of the methods of treatment provided herein, the ICOSxPD-1 antibody is a biosimilar of XmAb®23104. In yet other specific embodiments of the methods of treatment provided herein, the ICOSxPD-1 antibody is a bioequivalent of XmAb®23104.

3 BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 depicts the structure of the ICOSxPD-1 antibody of the disclosure. The

ICOSxPD-1 antibody has a 1 + 1 Fab-scFv-Fc format (also referred to as the “triple F” format or “bottle opener” format). Bottle opener format antibodies include a) a first monomer that includes a first Fc domain and an scFv region, wherein the scFv includes a first variable heavy chain and a first variable light chain (also referred herein as a “scFv-Fc heavy chain”); b) a second monomer that includes a VH-CHl-hinge-CH2-CH3, wherein VH is a second variable heavy chain and CH2 and CH3 is a second Fc domain (also referred herein as a “Fab-Fc heavy chain”); and c) a light chain that includes a second variable light chain. As shown in FIG. 1, the scFv is the PD-1 binding domain and the second variable heavy chain and second variable light chain comprise the TCOS binding domain. In some cases, the scFv is the TCOS binding domain and the second variable heavy chain and second variable light chain comprise the PD-1 binding domain. [0024] FIG. 2 depicts a schematic of the study design for treating solid tumors using an ICOSxPD-1 antibody of the disclosure.

[0025] FIG. 3 depicts a study design where an ICOSxPD-1 antibody of the disclosure is administered on days 1 and 15 of each cycle and RECIST 1.1 is evaluated every eight weeks. [0026] FIG. 4 depicts a graph showing treatment-related adverse events (TRAEs; on the right) and the subset of immunotherapy-related adverse events (irAEs; on the left).

[0027] FIGS. 5A-5C depict pharmacokinetics data associated with an ICOSxPD-1 antibody of the disclosure. FIG. 5A shows PK curves from the (remote) pembrolizumab at doses from 0.002 to 15 mg/kg of an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104). FIG. 5B shows PK curves from the (recent) pembrolizumab cohorts at doses from 0.06 to 10 mg/kg. FIG. 5C shows PK curves from the remote and recent cohorts at 10 mg/kg. [0028] FTG. 6 depicts results from a receptor occupancy assay showing 100% saturation of receptor at 0.6 mg/kg and higher doses of an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104).

[0029] FIGS. 7A-7C depict results from treatment with an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104). FIG. 7A and FIG. 7B also depict scans showing a decrease in the size of the solid tumors after patients are treated with an ICOSxPD-1 antibody of the disclosure as compared to baseline (e.g., at Cycle 4, Day 26 for FIG. 7A; and at Cycle 2, Day 26 for FIG. 7B)

4 DETAILED DESCRIPTION

4.1 Definitions

[0030] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. [0032] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0033] As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. In some cases, the numerical disclosed throughout can be “about” that numerical value even without specifically mentioning the term “about.”

[0034] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. [0035] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the invention.

[0036] As used herein, and unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0037] As used herein, the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or.” [0038] As used herein, the term “cycle” refers to a specified period of time during which a treatment (e.g., an ICOSxPD-1 antibody) is administered to a subject. For example, one cycle can last a specific number of days, weeks, or months. In a specific embodiment, one cycle lasts 28 days. A treatment (e.g., an ICOSxPD-1 antibody) can be administered to a subject for one cycle or for multiple cycles. When a treatment is administered to a subject for multiple cycles, the cycles can occur at regular intervals. For example, a cycle can be immediately followed by one or more additional cycles, or two or more cycles can be separated by a period without treatment. In an embodiment, the subject is administered a treatment for two cycles.

[0039] As used herein, “ICOS,” also known as “Inducible T Cell Costimulator,” “AILIM,” “Activation-Inducible Lymphocyte Immunomediatory Molecule,” “Inducible T-Cell Costimulator,” “CD278,” “Inducible T-Cell Co-Stimulator,” “Inducible Costimulator,” “CD278 Antigen,” and “CVID1,” refers to a costimulatory molecule that is expressed on activated T cells and belongs to the CD28 and CTLA-4 cell-surface receptor family (e.g., HGNC: 5351; NCBI Entrez Gene: 29851; Ensembl: ENSG00000163600; OMIM®: 604558; UniProtKB/Swiss-Prot: Q9Y6W8). ICOS plays a role in T-cell responses, including cell signaling, immune responses, and proliferation. In a specific embodiment, the ICOS is human ICOS. [0040] As used herein, “PD-1,” also known as “PD1,” “CD279,” “HSLE1,” “PD-1,” “Systemic Lupus Erythematosus Susceptibility,” “Programmed Cell Death Protein 1,” “Protein PD-1,” “SLEB2,” “HPD-1,” “Programmed Cell Death 1 Protein,” “CD279 Antigen,” and “HPD- L,” refers to an immune-inhibitory receptor expressed in activated T cell (e.g., HGNC: 8760; NCBI Entrez Gene: 5133; Ensembl: ENSG00000188389; OMIM®: 600244; UniProtKB/Swiss- Prot: QI 5116). PD-1 is involved in regulating T-cell functions. In a specific embodiment, the PD-1 is human PD-1.

[0041] The term “multispecific antibody,” as used herein, means any non-native or alternate antibody format that engages two or more different antigens (e.g., ICOS x PD-1 multispecific antibodies). In some embodiments, a multispecific antibody is a bispecific antibody.

[0042] As used herein, the term “antibody” is used in a broad sense and includes immunoglobulin or antibody molecules. In general, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. In specific embodiments, the antibodies provided herein are based on IgGl, IgG2, or IgG4. In some embodiments, the antibodies provided herein are based on IgGl, IgG2, or IgG4 and contain amino acid variants. In many preferred embodiments, the antibodies provided herein are based on human IgGl, and contain amino acid variants as outlined herein. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda, based on the amino acid sequences of their constant domains. In one embodiment, an antibody provided herein comprises a kappa light chain. In other embodiments, an antibody provided herein comprises a lambda light chain. In certain embodiments, an antibody provided herein comprises a kappa light chain and a lambda light chain. Accordingly, the antibodies provided herein can, in certain embodiments, contain a kappa light chain constant domain. In other embodiments, antibodies provided herein can, in certain embodiments, contain lambda light chain constant domains. In some embodiments, the antibodies provided herein can contain kappa light chain and lambda light chain constant domains.

[0043] In addition to the heavy and light constant domains, antibodies contain an antigenbinding region that is made up of a light chain variable (VL) domain (or region) and a heavy chain variable (VH) domain (or region). The term “hypervariable region”, such as a VH or VL, when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and/or form structurally defined loops. Generally, antibodies comprise six hypervariable regions; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3). A “CDR” refers to one of three hypervariable regions (VH CDR1, VH CDR2 or VH CDR3) within the non-framework region of the immunoglobulin (Ig or antibody) VH 0-sheet framework, or one of three hypervariable regions (VL CDR1, VL CDR2 or VL CDR3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. The light chain variable region CDR1 domain is interchangeably referred to herein as LCDR1 or VL CDR1. The light chain variable region CDR2 domain is interchangeably referred to herein as LCDR2 or VL CDR2. The light chain variable region CDR3 domain is interchangeably referred to herein as LCDR3 or VL CDR3. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR1 or VH CDR1. The heavy chain variable region CDR2 domain is interchangeably referred to herein as HCDR2 or VH CDR2. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR3 or VH CDR3.

[0044] A number of hypervariable region delineations are in use and are encompassed herein, for example, in the tables and/or Examples provided below. The “Kabaf ’ CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). “Chothia” refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-HCDR1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The “AbM” hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). “Contact” hypervariable regions are based on an analysis of the available complex crystal structures. An additional a universal numbering system can also be used, ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev. Comp. Immunol. 27(l):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, J. Mol. Biol. 309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lafranc et al., supra). An Exemplary system may also be used that combines Kabat and Chothia.

[0045] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LCDR1), 46-56 or 50-56 (LCDR2) and 89-97 or 89-96 (LCDR3) in the VL and 26-35 or 26-35A (HCDR1), 50-65 or 49-65 (HCDR2) and 93-102, 94-102, or 95-102 (HCDR3) in the VH. CDR sequences, reflecting each of the above numbering schemes, are provided herein.

[0046] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CHI, hinge, CH2 and CH3 regions of the heavy chain and the CL region of the light chain.

[0047] The term “framework” or “FR” residues are those variable region residues flanking the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.

[0048] The term “antigen binding domain” or “ABD” as used herein refer to a set of six CDRs that, when present as part of a polypeptide sequence, specifically binds a target antigen as discussed herein. As is known in the art, these CDRs are generally present as a first set of variable heavy CDRs (VH CDRs) and a second set of variable light CDRs (CDRs), each comprising three CDRs: VH CDR1, VH CDR2, VH CDR3 for the heavy chain and VL CDR1, VL CDR2 and VL CDR3 for the light. The CDRs are present in the variable heavy and variable light domains, respectively, and together form an Fv region. Thus, in some cases, the six CDRs of the antigen binding domain are contributed by a variable heavy and a variable light domain. In a “Fab” format, the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (containing the VH CDR1, VH CDR2 and VH CDR3) and the variable light domain (containing the VL CDR1, VL CDR2 and VL CDR3), with the C-terminus of the VH domain being attached to the N-terminus of the CHI domain of the heavy chain and the C- terminus of the VL domain being attached to the N-terminus of the constant light domain (and thus forming the light chain). In a scFv format, the VH and VL domains are covalently attached, generally through the use of a linker (a “scFv linker”) as outlined herein, into a single polypeptide sequence, which can be either (starting from the N-terminus) VH-linker-VL or VL- linker-VH (including optional domain linkers on each side, depending on the format used.

[0049] In general, the C-terminus of the scFv domain is attached to the N-terminus of a domain linker in the second monomer. In certain embodiments, the domain linker is a hinge. In some embodiments, the domain linker is a GS linker (single or multiple GS amino acids). In other embodiments, the domain linker is a truncated hinge.

[0050] As used herein, the term an “isolated antibody” refers to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to a given target is substantially free of antibodies that do not bind to that same target). Tn addition, an isolated antibody is substantially free of other cellular material and/or chemicals.

[0051] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies provided herein can be made by the hybridoma method, phage display technology, single lymphocyte gene cloning technology, or by recombinant DNA methods. For example, the monoclonal antibodies can be produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, such as a transgenic mouse or rat, having a genome comprising a human heavy chain transgene and a light chain transgene. In a specific embodiment, an ICOSxPDl antibody provided herein is a XmAb®23104 bispecific monoclonal antibody.

[0052] “Fab” or “Fab region” refers to the polypeptide that comprises the VH, CHI, VL, and CL immunoglobulin domains, generally on two different polypeptide chains (e.g., VH-CH1 on one chain and VL-CL on the other). Fab may refer to this region in isolation, or this region in the context of a bispecific antibody of the invention. In the context of a Fab, the Fab comprises an Fv region in addition to the CHI and CL domains.

[0053] As used herein, “Fv,” “Fv fragment,” or “Fv region” refer to a polypeptide that comprises the VL and VH domains of an ABD. Fv regions can be formatted as both Fabs (as discussed above, generally two different polypeptides that also include the constant regions as outlined above) and scFvs, where the VL and VH domains are combined (generally with a linker as discussed herein) to form an scFv.

[0054] The term “single chain Fv” or “scFv” refers to a variable heavy domain covalently attached to a variable light domain, generally using a scFv linker as discussed herein, to form a scFv or scFv domain. A scFv domain can be in either orientation from N- to C-terminus (VH- linker-VL or VL-linker-VH). The order of the VH and VL domain can be indicated in the name, e.g.,H.X_L.Y means N- to C-terminal is VH-linker-VL, and L.Y H.X is VL-linker-VH.

[0055] The terms “Fc,” “Fc region,” or “Fc domain” as used herein refer to the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgGl, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus the definition of “Fc domain” includes both amino acids 231 -447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof. An “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.) Human IgG Fc domains are of particular use in the present invention, and can be the Fc domain from human IgGl, IgG2 or IgG4.

[0056] As used herein, “heavy chain constant region” refers to the CHl-hinge-CH2-CH3 portion of an antibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgGl this is amino acids 118-447. As is known in the art, there can be C- terminal protease clipping during protein expression and thus the IgGl terminal lysine (K447), and additional residues, may be missing from the protein.

[0057] As used herein, the term “multispecific antibody” refers to an antibody that comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In an embodiment, the first and second epitopes are on different targets (e.g., the first epitope is on a first target (such as ICOS) and the second epitope is on a second target (such as PD1)).

[0058] As used herein, the term “bispecific antibody” refers to a multispecific antibody that binds no more than two antigens. A bispecific antibody is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In an embodiment, the first and second epitopes are on different targets (e.g., the first epitope is on a first target (such as ICOS) and the second epitope is on a second target (such as PD1)).

[0059] The invention provides a number of antibody domains that have sequence identity to human antibody domains. The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0060] Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J. (1988) “Improved Tools for Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) “Basic Local Alignment Search Tool,” J. Mol. Biol. 215:403-10 , the “BLAST” algorithm, see, e.g., blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc.) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters.

[0061] Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. [0062] Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89: 10915 (1989)).

[0063] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. NatT. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

[0064] The antibodies of the present invention are generally isolated or recombinant. “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.

[0065] As used herein, the terms “peptide,” “polypeptide,” or “protein” can refer to a molecule comprised of amino acids and can be recognized as a protein by those of skill in the art. The conventional one-letter or three-letter code for amino acid residues is used herein. The terms “peptide,” “polypeptide,” and “protein” can be used interchangeably herein to refer to polymers of amino acids of any length. The peptide sequences described herein are written according to the usual convention whereby the N-terminal region of the peptide is on the left and the C- terminal region is on the right. Although isomeric forms of the amino acids are known, it is the L-form of the amino acid that is represented unless otherwise expressly indicated.

[0066] As used herein, the terms “treat,” “treatment,” and “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with a solid malignant tumor described herein, or the improvement in the solid malignant tumor condition, or the improvement in the disease associated with the solid malignant tumor, or the increase in the immune system response of the human subject, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a solid malignant tumor described herein resulting from the administration of one or more therapies. In specific embodiments, the terms “treat,” “treatment,” and “treating” refer to the amelioration of at least one measurable physical parameter of a solid malignant tumor described herein, such as tumor size, rate of tumor growth, number of tumor cells, tumor invasiveness, presence of metastasis, or extent of metastasis. In other embodiments the terms “treat,” “treatment,” and “treating” refer to the inhibition of the progression of a solid malignant tumor described herein, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat,” “treatment,” and “treating” refer to an increase in the immune system response of the human subject, such as increased T cell infiltration, increased T cell activation, upregulation of IFN pathways, upregulation of antigen presentation pathway, or increased Ki67+ induction in T cells In an exemplary embodiment, treating a solid malignant tumor provides an improvement, or a lack of progression, in the disease associated with the tumor or the tumor condition, and/or an improvement, or a lack of progression, in the symptoms associated with the disease or condition. In a specific embodiment, the improvement, for example, is as compared to the symptoms before or without treatment. For example, treating a solid malignant tumor refers to one or more of the following: (1) a reduction in the size of the solid tumor or number of solid malignant tumor cells, (2) an increase in solid malignant tumor cell death; (3) inhibition of solid malignant tumor cell survival; (5) inhibition (i.e., slowing to some extent, preferably lack of progression) of solid malignant tumor growth, such as stable disease; (6) inhibition of solid malignant tumor cell metastasis; (7) an increase in progression- free survival; (8) an increase in overall survival rate; and (9) some relief from one or more symptoms associated with the disease or condition. Additional descriptions regarding treatment can be found in the RECIST criteria (Eisenhauer etal. (2009) Eur J Cancer. 45:228-47; Chalian et al. (2011) Radiographics 31 :2093-105); the imRECIST criteria (Hodi et al. (2018) J Clin Oncol. 36:850-858); the modified IrRC criteria (Wolchok etal. (2009) Clin Cancer Res. 15:7412-20); and the PCWG3 criteria (Scher, et al. (2016) Clin Oncol. 34: 1402-18). In some embodiments, treating a solid malignant tumor involves administering the bispecific antibody for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the bispecific antibody for yet another specific period of time. In some embodiments, treating a solid malignant tumor involves administering the bispecific antibody until one of the treatment effects described herein is achieved, pausing administration of the bispecific antibody while this treatment effect continues to be observed, and resuming administration of the bispecific antibody if this treatment effect ceases to be observed.

[0067] Solid malignant tumor treatment can be determined by standardized response criteria specific to the disease associated with the tumor or the tumor condition. Solid malignant tumor response can be assessed for changes in tumor morphology (i.e., with neo-adjuvant use of a therapy, such as assessment of pathological response) or tumor metrics (i.e., overall tumor burden, tumor size, and the like) using screening techniques such as magnetic resonance imaging (MRI) scan, positron emission tomography (PET) scan, x-radiographic imaging, radionuclide scan, computed tomographic (CT) scan, bone scan imaging, endoscopy, tumor sampling including bone marrow aspiration (BMA), and counting of tumor marker levels and/or tumor cells in the circulation.

[0068] Treatment according to the present invention includes a “therapeutically effective amount” of the medicaments used. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. Alternatively, this property of a composition may be evaluated by examining the ability of the compound to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound may decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject’s size, the severity of the subject’s symptoms, and the particular composition or route of administration selected.

[0069] The terms “patient,” “subject,” and “human subject” are used interchangeably herein. [0070] As used herein, a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge.

Families of amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). As used herein, a “non-conservative amino acid substitution” is one in which is not a conservative amino acid substitution.

4.2 Overview

[0071] Provided herein, in certain aspects, are methods for treating a solid tumor using an anti-ICOS x anti-PD-1 multispecific antibody (“ICOSxPD-1 antibody”). Also provided herein, are methods for treating a solid tumor using an ICOSxPD-1 antibody and an anti-CTLA4 antibody.

4.3 Pharmaceutical Compositions

Antibodies

[0072] Provided herein are methods of treating a solid tumor using a multispecific antibody (e.g., bispecific antibody), wherein the multispecific antibody comprises a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1 (“ICOSxPD- 1 antibody”). Also provided herein are methods of treating a solid tumor using a combination therapy. In certain embodiments, the combination therapy comprises an ICOSxPD-1 antibody and an anti-CTLA4 antibody. In a specific embodiment, the CTLA4 antibody is ipilimumab.

[0073] Amino acid sequences (Kabat CDRs) of exemplary ICOSxPD-1 antibodies are provided in Table 1 below. Table 1. Amino Acid Sequences of Exemplary TCOSxPD-1 Antibodies

[0074] In some embodiments, the ICOSxPD-1 antibody, has a “bottle opener” format (also referred to as the “triple F” format) as is generally depicted in FIG. 1. In this embodiment, the PD-1 antigen binding domain is the scFv in the bottle opener format and the ICOS antigen binding domain is the Fab in the bottle opener format. In some embodiments, the ICOS antigen binding domain is the scFv in the bottle opener format and the PD-1 antigen binding domain is the Fab in the bottle opener format.

[0075] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Kabat numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Exemplary numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Contact numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the IMGT numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the AbM numbering system. Exemplary sets of 6 CDRs (VH CDR1-3 and VL CDR1-3) of certain antibody embodiments are provided herein. Other sets of CDRs are contemplated and within the scope of the antibody embodiments provided herein. [0076] In one embodiment, the TCOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1. [0077] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1. [0078] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.

[0079] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1.

[0080] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.

[0081] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1 , VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.

[0082] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1, and a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence provided in Table 1, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence provided in Table 1.

[0083] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 13. [0084] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 14. [0085] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 13, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 14.

[0086] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1 , VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 19.

[0087] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the first antigen binding domain comprises a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:20. [0088] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 19, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:20.

[0089] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 13, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDR1, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO: 14, and a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH comprising a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence of a VH CDR1, VH CDR2 and VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 19, and a VL comprising a VL CDR1, VL CDR2 and VL CDR3 having an amino acid sequence of a VL CDRI, VL CDR2 and VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:20.

[0090] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH domain comprising a VH CDRI, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively. [0091] In one embodiment, the TCOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NON, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0092] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NON, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0093] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively.

[0094] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.

[0095] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.

[0096] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NON, SEQ ID NO:5, and SEQ ID NO:6, respectively, and the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.

[0097] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to one or more of any one of SEQ ID NOS: 1-3, and/or a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to one or more of any one of SEQ ID NOS:4-6, and/or the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to one or more of any one of SEQ ID NOS:7-9, and/or a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to one or more of any one of SEQ ID NOS: 10-12. In specific embodiments, such binding domains having less than 100% identity retain the function of binding to the respective target (e.g., ICOS or PD1) of the binding domain.

[0098] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1, wherein the first antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence comprising 1, 2, 3, or 4 amino acid modification(s) (e.g., substitution (conservative or non-conservative), deletion, or insertion) in one or more of any one of SEQ ID NOS: 1-3, and/or a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence comprising I, 2, 3, or 4 amino acid modification(s) (e.g., substitution (conservative or non-conservative), deletion, or insertion) in one or more of any one of SEQ ID NOS:4-6, and/or the second antigen binding domain comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence comprising 1, 2, 3, or 4 amino acid modification(s) (e.g., substitution (conservative or nonconservative), deletion, or insertion) in one or more of any one of SEQ ID NOS:7-9, and/or a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence comprising 1, 2, 3, or 4 amino acid modification(s) (e.g., substitution (conservative or nonconservative), deletion, or insertion) in one or more of any one of SEQ ID NOS: 10-12. In specific embodiments, such binding domains having 1, 2, 3 or 4 amino acid modifications retain the function of binding to the respective target (e.g., ICOS or PD1) of the binding domain. [0099] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 13. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 13. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 13. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 13. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 13. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 13.

[00100] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 14. In one embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO:14. In another embodiment, the first antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 14.

[00101] In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 14. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 14. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 14.

[001021 Iⁿ one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 19. In one embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.

[00103] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO:20. In one embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO:20. Tn another embodiment, the second antigen binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:20.

[00104] In one embodiment, the ICOSxPD-1 antibody comprises a second antigen binding domain that binds to PD-1, wherein the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO:20. In one embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:20.

[00105] In one In one embodiment, the ICOSxPD-1 antibody comprises a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1, wherein the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO:20. In one embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 90% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 95% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 98% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about or at least about 99% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the first antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 13 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 14, and the second antigen binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:20. [00106] In one embodiment, the ICOSxPD-1 antibody comprises a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15. In another embodiment, the ICOSxPD-1 antibody comprises a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16. In another embodiment, the ICOSxPD-1 antibody comprises a third monomer comprising, from N- to C- terminus, a VL-CL having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 17. In another embodiment, the ICOSxPD-1 antibody comprises a first monomer comprising, from N- to C-terminus, a scFv- linker-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15, a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16, and a third monomer comprising, from N- to C-terminus, a VL-CL having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 17.

[00107] In another embodiment, the ICOSxPD-1 antibody comprises a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15, and wherein the scFv-linker-CH2-CH3 comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and/or SEQ ID NO:9. In another embodiment, the ICOSxPD-1 antibody comprises a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15, and wherein the scFv-linker-CH2-CH3 comprises a VL CDR1, a VL CDR2, and/or a VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and/or SEQ ID NO: 12. In another embodiment, the ICOSxPD-1 antibody comprises a second monomer comprising, from N- to C- terminus, a VH-CHl-hinge-CH2-CH3 having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16, and wherein the VH-CHl-hinge-CH2-CH3 comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 having an amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and/or SEQ ID NO:3. In another embodiment, the ICOSxPD-1 antibody comprises a third monomer comprising, from N- to C- terminus, a VL-CL having the amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 17, and wherein the VL-CL comprises a VL CDR1, a VL CDR2, and/or a VL CDR3 having an amino acid sequence of SEQ ID NON, SEQ ID NO:5, and/or SEQ ID NO:6 [00108] In another embodiment, the TCOSxPD-1 antibody comprises a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15, a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2-CH3 comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16, and a third monomer comprising, from N- to C- terminus, a VL-CL comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 17.

[00109] In some embodiments, the scFv of the first monomer comprises: a VH CDR1 having the amino acid sequence of SEQ ID NO:7; a VH CDR2 having the amino acid sequence of SEQ ID NO:8; a VH CDR3 having the amino acid sequence of SEQ ID NOV; a VL CDR1 having the amino acid sequence of SEQ ID NO: 10; a VL CDR1 having the amino acid sequence of SEQ ID NO: 11 ; and/or a VL CDR3 having the amino acid sequence of SEQ ID NO: 12.

[00110] In some embodiments, the VH of the second monomer comprises: a VH CDR1 having the amino acid sequence of SEQ ID NO: 1; a VH CDR2 having the amino acid sequence of SEQ ID NO:2; and a VH CDR3 having the amino acid sequence of SEQ ID NO:3.

[00111] In some embodiments, the VL of the third monomer comprises: a VL CDR1 having the amino acid sequence of SEQ ID NON; a VL CDR2 having the amino acid sequence of SEQ ID NO:5; and a VL CDR3 having the amino acid sequence of SEQ ID NO:6.

[00112] In some embodiments, the scFv of the first monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8; a VH CDR3 comprising the amino acid sequence of SEQ ID NOV; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 10; a VL CDR1 comprising the amino acid sequence of SEQ ID NO:11; and/or a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[00113] In some embodiments, the VH of the second monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2; and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3.

[001141 In some embodiments, the VL of the third monomer comprises: a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4; a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6.

[00115] In some embodiments, the scFv of the first monomer comprises: a VH CDR1 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:7; a VH CDR2 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:8; a VH CDR3 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NON; a VL CDR1 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO: 10; a VL CDR1 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:11; and/or a VL CDR3 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO: 12.

[00116] In some embodiments, the VH of the second monomer comprises: a VH CDR1 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO: 1; a VH CDR2 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:2; and a VH CDR3 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:3.

[00117] In some embodiments, the VL of the third monomer comprises: a VL CDR1 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:4; a VL CDR2 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO:5; and a VL CDR3 comprising an amino acid sequence comprising an amino acid sequence comprising about or at least about 90%, about or at least about 95%, about or at least about 98%, about or at least about 99%, or about 100% sequence identity to SEQ ID NO: 6.

[00118] It will be understood that XmAb®23104 can be used in all of the methods of the invention provided here.

[00119] In a specific embodiment, the ICOSxPD-1 antibody of any of the methods provided herein is XmAb®23104. XmAb®23104 comprises a first monomer comprising, from N- to C- terminus, a scFv-linker-CH2-CH3 having the amino acid sequence of SEQ ID NO: 15, a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2-CH3 having the amino acid sequence of SEQ ID NO: 16, and a third monomer comprising, from N- to C-terminus, a VL-CL having the amino acid sequence of SEQ ID NO: 17. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody is a biosimilar of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody is a bioequivalent of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH CDR1, VH CDR2, and VH CDR3 of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VL CDR1, VL CDR2, and VL CDR3 of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH CDR1, VH CDR2, and VH CDR3 of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VL CDR1, VL CDR2, and VL CDR3 of the PD-1 binding domain of XmAb®23104. Tn one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH CDR1, VH CDR2, and VH CDR3 of the ICOS binding domain of XmAb®23104, and a VL CDR1, VL CDR2, and VL CDR3 of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH CDR1, VH CDR2, and VH CDR3 of the PD-1 binding domain of XmAb®23104, and a VL CDR1, VL CDR2, and VL CDR3 of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH CDR1, VH CDR2, and VH CDR3 of the ICOS binding domain of XmAb®23104, a VL CDR1, VL CDR2, and VL CDR3 of the ICOS binding domain of XmAb®23104, a VH CDR1, VH CDR2, and VH CDR3 of the PD-1 binding domain of XmAb®23104, and a VL CDR1, VL CDR2, and VL CDR3 of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VL of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VL of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH of the ICOS binding domain of XmAb®23104, and a VL of the ICOS binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH of the PD-1 binding domain of XmAb®23104, and a VL of the PD-1 binding domain of XmAb®23104. In one embodiment of the methods provided herein, the ICOSxPD-1 antibody comprises an amino acid sequence of a VH of the ICOS binding domain of XmAb®23104, a VL of the ICOS binding domain of XmAb®23104, a VH of the PD-1 binding domain of XmAb®23104, and a VL of the PD-1 binding domain of XmAb®23104.

4.4 Methods of Treatment

[00120] The methods provided herein are useful for the treatment of solid tumors, including, but not limited to undifferentiated pleomorphic sarcoma, non-squamous non-small cell lung carcinoma, soft-tissue sarcoma, myxofibrosarcoma, head and neck squamous cell carcinoma, colorectal cancer, renal cell carcinoma, clear cell histology, melanoma, cervical carcinoma, pancreatic carcinoma, estrogen receptor, progesterone receptor, Her2 negative breast cancer, hepatocellular carcinoma, urothelial carcinoma, nasopharyngeal carcinoma, endometrial carcinoma, small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, and/or sarcoma. In some embodiments, a solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is non-squamous non-small cell lung carcinoma (NSCLC). In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is head and neck squamous cell carcinomas (HNSCC). In some embodiments, the solid tumor is nasopharyngeal carcinoma (NPC). In some embodiments, the solid tumor is colorectal cancer (CRC). In some embodiments, the solid tumor is renal cell carcinoma. In some embodiments, the solid tumor is undifferentiated pleomorphic sarcoma (UPS). In some embodiments, the solid tumor is a soft-tissue sarcomas (STS). In some embodiments, the solid tumor is a high-grade soft-tissue sarcomas (STS). In some embodiments, the solid tumor is myxofibrosarcoma (MFS). In some embodiments, the solid tumor is clear cell histology (ccRCC). In some embodiments, the subject has been diagnosed with or is at risk of developing one or at least one solid tumor. In some embodiments, the subject has been diagnosed with or is at risk of developing two or more solid tumors.

[00121] In an exemplary embodiment, provided herein are methods for treating a solid tumor in a human subject comprising administering to the subject an ICOSxPD-1 antibody of the disclosure. In some embodiments, a human subject is a juvenile. In some embodiments, a human subject is a under the age of 18. In some embodiments, a human subject is 18 or older. In some embodiments, a human subject is a female subject. In some embodiments, a human subject is a male subject. In some embodiments, a human subject is about or at least about 5, 10, 15, 18, 20, 21, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or more than 90 years of age. In some embodiments, a subject is a treatment-naive subject. In some embodiments, a subject has received previous therapy for the solid tumor. In some embodiments, a subject has received previous therapy and has demonstrated disease progression on previous therapy. In some embodiments, previous therapy is any suitable therapy for treating a solid tumor. Non-limiting examples of previous therapy includes an anti-PD-1 monotherapy, platinum-containing combination chemotherapy, anti-cancer therapy, PD-L1 therapy, and/or PD-L2 therapy. In some embodiments, the previous therapy comprises or consists of treatment with pembrolizumab, carboplatin, pemetrexed, cisplatin, atezolizumab, paclitaxel, bevacizumab, cemiplimab-rwlc, nivolumab, cisplatin-based chemotherapy, carboplatin-based chemotherapy, afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, ceritinib, crizotinib, dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and/or binimetinib. In some embodiments, the previous therapy is pembrolizumab. In some embodiments, a subject is not treated with an anti-PD-1 antibody within 6 weeks before the start of a method of the disclosure.

[00122] In one embodiment, the solid tumor is refractory, relapsed, or refractory and relapsed solid tumor. In another embodiment, the solid tumor is a newly diagnosed solid tumor.

[00123] In one embodiment, the solid tumor comprises an elevated ICOS expression level compared to a reference. In another embodiment, the reference is the ICOS expression level obtained from a biological sample from the subject at an earlier time point. In another embodiment, the reference is the ICOS expression level in a biological sample from another subject or a population of subjects diagnosed with the same solid tumor as the subject. In another embodiment, the reference is the ICOS expression level in a biological sample from another subject or a population of subjects diagnosed with the same type and stage of the solid tumor as the subject. In another embodiment, the reference is a predetermined value. In another embodiment, the biological sample is a tumor sample. In another embodiment, the biological sample is a biopsy from the solid tumor. In another embodiment, the biological sample is serum. In another embodiment, the biological sample is a plasma sample. In another embodiment, the biological sample is a blood sample.

[00124] It will be understood that XmAb®23104 can be used in any of the methods of the invention provided herein.

[00125] It will also be understood that a biosimilar of XmAb®23104 can be used in any of the methods of the invention provided herein.

[00126] It will further be understood that a bioequivalent of XmAb®23104 can be used in any of the methods of the invention provided herein.

[00127] In some embodiments, a method of the disclosure comprises administering an ICOSxPD-1 antibody of the disclosure to a subject as a monotherapy. In some embodiments, an ICOSxPD-1 antibody of the disclosure is administered to a subject as a monotherapy for treating the solid tumor. As used herein, the term “monotherapy” refers to the use of a single agent (e.g, ICOSxPD-1 antibody of the disclosure), without a second active agent, to treat the same indication, e.g., the same solid tumor. In some embodiments, the term “monotherapy” does not exclude one or more additional agent(s) from being administered to a subject if the one or more additional agent(s) is/are not administered for treating the same solid tumor in the subject. For example, in some embodiments, the term “monotherapy” does not exclude one or more additional agent(s) used to prevent or ameliorate injection site side effects, fever, and/or any other side effect associated with the ICOSxPD-1 antibody of the disclosure from being administered to a subject. In some embodiments, the term “monotherapy” does not exclude treatment with one or more additional agent(s) used for treating or ameliorating another disease or disorder in the subject (e.g., a disease or disorder that is not the solid tumor that the ICOSxPD-1 antibody of the disclosure is being used to treat). In some embodiments, the another disease or disorder in the subject is another cancer that is not a solid tumor. In some embodiments, the another disease or disorder in the subject is another cancer that is not the solid tumor that the ICOSxPD-1 antibody of the disclosure is being used to treat. In some embodiments, the term “monotherapy” does not exclude previous treatment with another agent that was used for treating or attempting to treat a solid tumor in a subject (e.g, a subject undergoing monotherapy treatment with an ICOSxPD-1 antibody of the disclosure can be a subject that was previously treated with another agent for the solid tumor). In some embodiments, a subject receiving monotherapy treatment with an ICOSxPD-1 antibody of the disclosure is a subject with relapsed, refractory, or relapsed and refractory solid tumor. In some embodiments, a subject receiving monotherapy treatment with an ICOSxPD-1 antibody of the disclosure is a subject with a solid tumor that is resistant to agents that were previously used for treating the solid tumor. In some embodiments, the term “monotherapy” does not exclude previous treatment with another agent prior to the first dose of an ICOSxPD- I antibody of the disclosure. In some embodiments, the term “monotherapy” does not exclude premedication (e.g., premedication with antihistamine, acetaminophen, hypertension agents, steroids, and the like). [00128] In some embodiments, a method of the disclosure comprises administering an ICOSxPD-1 antibody of the disclosure and an antibody that binds CTLA-4 (CTLA-4 antibody). It will be understood that ipilimumab can be further administered in all methods of the invention as provided herein. In some embodiments, a method of the disclosure comprises administering an TCOSxPD-1 antibody of the disclosure, a (CTLA-4 antibody), and one or more additional agent(s). In some embodiments of any of the methods of treatment provided herein, the CTLA-4 antibody is ipilimumab. In some embodiments of any of the methods of treatment provided herein, the CTLA-4 antibody is a biosimilar of ipilimumab. In some embodiments of any of the methods of treatment provided herein, the CTLA-4 antibody is a bioequivalent of ipilimumab. In some embodiments, the CTLA-4 antibody is tremelimumab. In some embodiments, the CTLA-4 antibody is ipilimumab, tremelimumab, BMS-986218, MK-1308, ADU-1604, BMS- 986249, CS-1002, BCD- 145, and/or REGN-4659. In some embodiments, the CTLA-4 antibody is any CTLA-4 antibody known in the art. In some embodiments, the CTLA-4 antibody is administered before the ICOSxPD-1 antibody of the disclosure is administered to a subject. In some embodiments, on the days that both the CTLA-4 antibody and the ICOSxPD-1 antibody of the disclosure are administered to a subject, the CTLA-4 antibody is administered to the subject before the ICOSxPD-1 antibody of the disclosure.

[00129] In a specific embodiment of any of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00130] In another aspect, provided herein is a method of treating a solid tumor in a subject, wherein the method comprises: administering to the subject a first polypeptide comprising a first means capable of binding to ICOS and a second means capable of binding to PD-1. In some embodiments, the method of treatment further comprises administering to the subject a second polypeptide comprising a third means capable of binding to CTLA-4. In some embodiments, the first means is an ICOS antigen binding domain. In some embodiments, the second means is a PD-1 antigen binding domain. In certain embodiments, the first polypeptide is a multispecific antibody. In one embodiment, the multispecific antibody is a bispecific antibody. In a specific embodiment, the bispecific antibody is an ICOSxPD-1 bispecific antibody. In certain embodiments, the ICOSxPD-1 antibody is XmAb®23104. In one embodiment, the third means is a CTLA-4 binding domain. In some embodiments, the second polypeptide is a CTLA-4 antibody. In certain embodiments, the CTLA-4 antibody is ipilimumab. In some embodiments, the subject is a subject in need thereof.

Dosage Regimens

[00131] In one aspect, an ICOSxPD-1 antibody of the disclosure is administered according to a dosage regimen provided herein. In some embodiments, the ICOSxPD-1 antibody of the disclosure is administered as a monotherapy. Tn some embodiments, the TCOSxPD-1 antibody of the disclosure is administered in combination with an CTLA-4 antibody. In some embodiments, an CTLA-4 antibody is administered according to a dosage regimen provided herein. However, the ICOSxPD-1 antibody and/or the CTLA-4 antibody can be administered by any method known in the art. One skilled in the art would appreciate that the route and/or mode of administration may vary depending upon the desired results.

[00132] In one embodiment, provided herein is a method comprising a dosing regimen for use in the study design provided in FIG. 2. In yet another embodiment, provided herein is a method comprising a dosing regimen provided in Example 1 and/or Example 2 of the disclosure.

[00133] In one embodiment, the method comprises cyclic administration of the ICOSxPD-1 antibody of the disclosure. In one embodiment of the methods provided herein, each cycle of the cyclic administration is 28 days. In some embodiments, each cycle of the cyclic administration is about, at least about, or at most about: 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 40 days, 45 days, or longer than 45 days. In some embodiments, each cycle of the cyclic administration is at least about 26 days. In some embodiments, each cycle of the cyclic administration is at least about 27 days. In some embodiments, each cycle of the cyclic administration is at most about 29 days. In some embodiments, each cycle of the cyclic administration is at most about 30 days. In some embodiments, each cycle of the cyclic administration is about 28 days. In some embodiments, each cycle is 28 days. In some embodiments, each cycle is followed by a period of rest (e.g, a period in which no drug or treatment is administered to a subject). In some embodiments, the period of rest is about, at least about, or at most about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more than 30 days. In some embodiments, the period of rest is at most about 15 days. In some embodiments, the period of rest is at most about 14 days. In some embodiments, the period of rest is at least about 10 days. In some embodiments, the period of rest is at least about 11 days. In some embodiments, the period of rest is about 13 days. In some embodiments, the period of rest is about 6 days. In some embodiments, the period of rest is about 8 days. In some embodiments, each cycle is about 28 days and the period of rest is about 7 days. In some embodiments, the ICOSxPD-1 antibody is administered to a subject four times in a cycle followed by a period of rest. Tn some embodiments, the TCOSxPD-1 antibody is administered to a subject twice in a cycle followed by a period of rest. In some embodiments, the ICOSxPD-1 antibody is administered to a subject three times in a cycle followed by a period of rest. In some embodiments, the ICOSxPD-1 antibody is administered to a subject once in a cycle followed by a period of rest. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00134] In some embodiments of the methods provided herein, the cyclic administration has about, at least about, or at most about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 cycle, or more than 30 cycles. In another embodiment, the cyclic administration comprises about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles, or more than twelve cycles. In another embodiment, the cyclic administration comprises about one cycle. In another embodiment, the cyclic administration comprises about two cycles. In another embodiment, the cyclic administration comprises about three cycles. In another embodiment, the cyclic administration comprises about four cycles. In another embodiment, the cyclic administration comprises about five cycles. In another embodiment, the cyclic administration comprises about six cycles. In another embodiment, the cyclic administration comprises about seven cycles. In another embodiment, the cyclic administration comprises about eight cycles. In another embodiment, the cyclic administration comprises about nine cycles. In another embodiment, the cyclic administration comprises about ten cycles. In another embodiment, the cyclic administration comprises about eleven cycles. In another embodiment, the cyclic administration comprises about twelve cycles. In another embodiment, the cyclic administration comprises more than twelve cycles. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00135] In one embodiment, the ICOSxPD-1 antibody is administered once in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered twice in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered three times in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered four times in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered five times in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered six times in each cycle. In another embodiment, the ICOSxPD-1 antibody is administered seven times in each cycle. In another embodiment, the TCOSxPD-1 antibody is administered eight times in each cycle. Tn some embodiments, the frequency of administration of the ICOSxPD-1 antibody varies between cycles. For example, in some embodiments, the ICOSxPD-1 antibody is administered to a subject twice in a cycle and administered once to a subject in another cycle. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00136] In some embodiments, the ICOSxPD-1 antibody is administered to the subject every: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than every 21 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every five days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every six days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every seven days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every eight days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every nine days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every ten days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every eleven days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every twelve days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject thirteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every fourteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every fifteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every sixteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every seventeen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every eighteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every nineteen days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every week. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every other week. In some embodiments, the ICOSxPD-1 antibody is administered to the subject once in two weeks. In some embodiments, the ICOSxPD-1 antibody is administered to the subject twice in two weeks. In some embodiments, the ICOSxPD-1 antibody is administered to the subject three times in three weeks. In some embodiments, the ICOSxPD-1 antibody is administered to the subject four times in four weeks. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 4-18 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 5-9 days. In some embodiments, the TCOSxPD-1 antibody is administered to the subject every 6-8 days. Tn some embodiments, the ICOSxPD-1 antibody is administered to the subject every 12-18 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 11-20 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 13-17 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 14-19 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 15-16 days. In some embodiments, the ICOSxPD-1 antibody is administered to the subject every 15 days. In one embodiment, the ICOSxPD-1 antibody is administered to the subject on day(s) 1, 8, 15, and/or 22 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day(s) 1, 8, 15, and 22 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day(s) 1, 8, 15, or 22 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 1 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 2 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 6 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 7 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 8 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 9 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 10 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 11 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 12 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 13 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 14 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 15 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 16 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 17 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 18 of a cycle of the cyclic administration. Tn another embodiment, the ICOSxPD-1 is administered to the subject on day 19 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 20 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 21 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on day 22 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 23 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 is administered to the subject on day 24 of a cycle of the cyclic administration. In another embodiment, the ICOSxPD-1 antibody is administered to the subject on days 1 and 15 of a cycle of the cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject between Day 14 and Day 16 of the first cycle of the cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject between Day 26 of the first cycle and Day 4 of the second cycle of the cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject between Day 12 and Day 18 of the second cycle of a cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject between Day 12 and Day 18 of the third cycle, and/or any consecutive cycle of a cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject between Day 26 of the second cycle or any subsequent cycle and Day 4 of the third cycle or any subsequent cycle of a cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to a subject on Day 1 of the first cycle and on Day 15 of the first cycle. In some embodiments, the ICOSxPD-1 antibody is administered to a subject on Day 1 of the second cycle and on Day 15 of the second cycle. In some embodiments, the ICOSxPD-1 antibody is administered to a subject on Day 1 of the third cycle and on Day 15 of the third cycle. In some embodiments, the ICOSxPD-1 antibody is administered to a subject on Day 1 and on Day 15 of any cycle, or of cycle four and/or onwards. In some embodiments, the ICOSxPD-1 antibody is administered to a subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of a cyclic administration. In some embodiments, an ICOSxPD-1 antibody is administered at the same dosage (e.g., 0.002 mg/kg, 0.02 mg/kg, 0.06 mg/kg, 0.2 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg) on the days that the TCOSxPD-1 antibody is administered to a subject. Tn some embodiments, an TCOSxPD-1 antibody is administered at a different dosage on at least one day of the days that the ICOSxPD-1 antibody is administered to a subject. In some embodiments, an ICOSxPD-1 antibody is administered at an escalating or gradual dosage (e.g., the first dosage is lower than a later dosage). In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00137] In one embodiment, the ICOSxPD-1 antibody is administered to the subject once every week. In another embodiment, the ICOSxPD-1 antibody is administered to the subject twice every week. In another embodiment, the ICOSxPD-1 antibody is administered to the subject once every two weeks. In another embodiment, the ICOSxPD-1 antibody is administered to the subject once every three weeks. In another embodiment, the ICOSxPD-1 antibody is administered to the subject once every four weeks. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00138] In one embodiment, the ICOSxPD-1 antibody is administered to the subject for about or at least about 4 weeks. In another embodiment, the ICOSxPD-1 antibody is administered to the subject for about or at least about 8 weeks, the ICOSxPD-1 antibody is administered to the subject for about or at least about 12 weeks, the ICOSxPD-1 antibody is administered to the subject for about or at least about 16 weeks, the ICOSxPD-1 antibody is administered to the subject for more than about 16 weeks. In one embodiment, the ICOSxPD-1 antibody is administered to the subject for about, at least about, or at most about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 moths, or more than 24 months. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[00139] In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg to about 50 mg/kg per day. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg to about 30 mg/kg per day. In one embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg to about 20 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 0.002 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 0.02 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 0 06 mg/kg per day. Tn another embodiment, the TCOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 0.2 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 0.6 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 1 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 1.8 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 5 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 5.4 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 10 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 15 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 20 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 25 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 30 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 35 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 40 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 45 mg/kg per day. In another embodiment, the ICOSxPD-1 antibody is administered to the subject in an amount of about, at least about, or at most about 50 mg/kg per day. In some embodiments, the dosage varies between one administration to another (e.g., between first and second dose, first and third dose, or between any dosage). In some embodiments, a lower dose is administered as a first dose to the subject. In some embodiments, the ICOSxPD-1 antibody is administered to a subject in an incrementing dose between administrations (z.e., dose escalation). In some embodiments, a dosage is increased from an administration to the following administration (e.g., if no severe side effects are observed). In some embodiments, a dosage is decreased between administrations (e.g., if severe side effects are observed). Tn a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104.

[001401 Iⁿ certain embodiments of the methods provided herein, the method further comprises administration of a second antibody, wherein the second antibody is a CTLA-4 antibody. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104, and the method further comprises administration of a second antibody, wherein the second antibody is ipilimumab.

[00141] In one embodiment, the ICOSxPD-1 antibody is administered as a monotherapy. In some embodiments, a CTLA-4 antibody is not administered to a subject. In a specific embodiment, the ICOSxPD-1 antibody is XmAb®23104. In other embodiments, the ICOSxPD-1 antibody is administered in combination with a CTLA4 antibody. In a one embodiment, the ICOSxPD-1 antibody is administered in combination with ipilimumab. In a specific embodiment of the various methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and administered in combination with the CTLA4 antibody ipilimumab.

[00142] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 0.5 mg/kg per day. In one embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 0.6 mg/kg per day. In one embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 0.7 mg/kg per day. In one embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 0.8 mg/kg per day. In one embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 0.9 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1.1 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1.2 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1.3 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1.4 mg/kg per day. Tn another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 1.5 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 2 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 2.5 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 3 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 4 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 5 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 6 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 7 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 8 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 9 mg/kg per day. In another embodiment, the CTLA-4 antibody is administered to the subject in an amount of about, at least about, or at most about 10 mg/kg per day. In some embodiments, the CTLA-4 antibody is administered to the subject in an amount of about 0.5 mg/kg to about 3 mg/kg. In some embodiments, the CTLA-4 antibody is administered to the subject in an amount of about 0.5 mg/kg to about 2 mg/kg. In some embodiments, the CTLA-4 antibody is administered to the subject in an amount of about 0.5 mg/kg to about 1.5 mg/kg. In some embodiments, the CTLA-4 antibody is administered to the subject in an amount of about 1 mg/kg to about 3 mg/kg. In some embodiments, the CTLA-4 antibody is administered to the subject in an amount of about 0.5 mg/kg to about 1 mg/kg. In some embodiments, the dosage varies between one administration to another (e.g., between first and second dose, first and third dose, or between any dosage). In some embodiments, the lower dose is administered as the first dose to the subject. In some embodiments, the CTLA-4 antibody is administered to the subject in an incrementing dose between administrations (i.e., dose escalation). In some embodiments, the dosage is increased from an administration to the following administration (e.g., if no severe side effects are observed). In some embodiments, the dosage is decreased between administrations (e.g., if severe side effects are observed). In some embodiments, the dosage for the CTLA-4 antibody is any suitable dosage for any CTLA-4 antibody, such as ipilimumab, tremelimumab, BMS-986218, MK-1308, ADU-1604, BMS- 986249, CS-1002, BCD- 145, and/or REGN-4659. In some embodiments, the dosage for the CTLA-4 antibody is the recommended dosage for any CTLA-4 antibody, including but not limited to, ipilimumab, tremelimumab, BMS-986218, MK-1308, ADU-1604, BMS-986249, CS- 1002, BCD-145, and/or REGN-4659. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00143] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered once in each cycle. In another embodiment, the CTLA-4 antibody is administered twice in each cycle. In another embodiment, the CTLA-4 antibody is administered three times in each cycle. In another embodiment, the CTLA-4 antibody is administered four times in each cycle. In another embodiment, the CTLA-4 antibody is administered five times in each cycle. In another embodiment, the CTLA-4 antibody is administered six times in each cycle. In another embodiment, the CTLA-4 antibody is administered seven times in each cycle. In another embodiment, the CTLA-4 antibody is administered eight times in each cycle. In one embodiment, the CTLA-4 antibody is administered three times in two cycles. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00144] In some embodiments of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered to the subject every: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than every 21 days. In some embodiments, the CTLA-4 antibody is administered to the subject every five days. In some embodiments, the CTLA-4 antibody is administered to the subject every six days. In some embodiments, the CTLA-4 antibody is administered to the subject every seven days. In some embodiments, the CTLA-4 antibody is administered to the subject every eight days. In some embodiments, the CTLA-4 antibody is administered to the subject every nine days. In some embodiments, the CTLA-4 antibody is administered to the subject every ten days.

In some embodiments, the CTLA-4 antibody is administered to the subject every 20 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 21 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 22 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 23 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 25 days. In some embodiments, the CTLA-4 antibody is administered to the subject every week. In some embodiments, the CTLA-4 antibody is administered to the subject every other week. In some embodiments, the CTLA-4 antibody is administered to the subject once in two weeks. In some embodiments, the CTLA-4 antibody is administered to the subject twice in two weeks. In some embodiments, the CTLA-4 antibody is administered to the subject three times in three weeks. In some embodiments, the CTLA-4 antibody is administered to the subject four times in four weeks. In some embodiments, the CTLA-4 antibody is administered to the subject once every 20-23 days. In some embodiments, the CTLA-4 antibody is administered to the subject once every 19-25 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 4-26 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 4-24 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 4-22 days. In some embodiments, the CTLA-4 antibody is administered to the subject every 5-9 days. In some embodiments, the CTLA-4 antibody is administered to the subject between Day 14 and Day 16 of the first cycle of the cyclic administration. In some embodiments, the CTLA-4 antibody is administered to the subject between Day 26 of the second cycle and Day 4 of the third cycle of the cyclic administration. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab. [00145] In some embodiments of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered to the subject before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 1 day before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 2 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 3 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 4 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 5 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 6 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 7 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 8 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 9 days before the first cycle of a cyclic administration. In some embodiments, the first dose of the CTLA-4 antibody is administered about or at least about 10 days before the first cycle of a cyclic administration. In some embodiments, the CTLA-4 antibody is administered about or at least about 1 day before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 2 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 3 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 4 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 5 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 6 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 7 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 8 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 9 days before the first dose of the ICOSxPD-1 antibody. In some embodiments, the CTLA-4 antibody is administered about or at least about 10 days before the first dose of the ICOSxPD-1 antibody. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00146] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered to the subject once every week. In another embodiment, the CTLA-4 antibody is administered to the subject twice every week. Tn another embodiment, the CTLA-4 antibody is administered to the subject once every two weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every three weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every four weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every five weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every six weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every seven weeks. In another embodiment, the CTLA-4 antibody is administered to the subject once every eight weeks. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00147] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, at most about 1 dose of the CTLA-4 antibody is administered in 8 weeks. In another embodiment, at most about 2 doses of the CTLA-4 antibody are administered in 8 weeks. In another embodiment, at most about 3 doses of the CTLA-4 antibody are administered in 8 weeks. In another embodiment, at most about 4 doses of the CTLA-4 antibody are administered in 8 weeks. In another embodiment, 4 doses of the CTLA-4 antibody are administered in 9 weeks. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00148] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered at most 1 time for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 2 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 3 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 4 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 5 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 6 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 7 times for the duration of the treatment. In another embodiment, the CTLA-4 antibody is administered at most 8 times for the duration of the treatment. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. Tn a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00149] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered at most 1 time in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 2 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 3 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 4 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 5 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 6 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 7 times in each cycle. In another embodiment, the CTLA-4 antibody is administered at most 8 times in each cycle. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00150] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered on the same day as the ICOSxPD-1 antibody of the disclosure. In one embodiment, the CTLA-4 antibody is administered about or at least about 30 minutes before the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about or at least about 60 minutes before the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about or at least about 90 minutes before the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about: 30 minutes, 90 minutes, 1 hour (hr), 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 10 hrs, 14 hrs, 18 hrs, 20 hrs, 22 hrs, or 24 hrs before the ICOSxPD-1 antibody is administered to the subject. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00151] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered on a different day than the TCOSxPD-1 antibody. Tn another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 1 day prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 2 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 3 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 4 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 5 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 6 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 7 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 8 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 9 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 10 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 11 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 12 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 13 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered about, at least about, or at most about 14 days prior to the ICOSxPD-1 antibody is administered to the subject. In another embodiment, the CTLA-4 antibody is administered more than 14 days prior to the ICOSxPD-1 antibody is administered to the subject. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab. [00152] In some embodiments of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered to the subject on Day 15 of the first cycle of the cyclic administration. In some embodiments, the CTLA-4 antibody is administered to the subject on Day 8 of the second cycle of the cyclic administration. In some embodiments, the CTLA-4 antibody is administered to the subject on Day 1 of the third cycle of the cyclic administration. In some embodiments, the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. In some embodiments, the ICOSxPD-1 antibody is administered to the subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of a cyclic administration; and a CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle of the cyclic administration, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of a cyclic administration. In some embodiments, the dosage for the ICOSxPD-1 antibody is 10 mg/kg. In some embodiments, the dosage for the CTLA-4 antibody is 1 mg/kg. In certain embodiments of the methods provided herein, the CTLA-4 antibody is ipilimumab. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104 and the CTLA-4 antibody is ipilimumab.

[00153] In certain embodiments of the methods provided herein comprising administration of an ICOSxPD-1 antibody, a cycle is 28 days long and consists of 2 doses of ICOSxPD-1 antibody on days 1 and 15. In certain embodiments of the methods provided herein comprising administration of an XmAb®23104 antibody, a cycle is 28 days long and consists of 2 doses of XmAb®23104 antibody on days 1 and 15. The permitted dosing window(s) can vary from plus or minus 1 to 3 days. In some embodiments of the methods provided herein comprising administration of an ICOSxPD-1 antibody, the ICOSxPD-1 antibody is XmAb®23104, and the method further comprises administration of a CTLA-4 antibody, wherein the CTLA-4 antibody is ipilimumab. In some embodiments, the ipilimumab is administered every 3 weeks. In certain embodiments, three induction doses of ipilimumab are administered in two 28 day cycles. In a specific embodiment of the methods provided herein, (i) XmAb®23104 is intravenously administered to the subject on days 1 and 15 of each 28 day cycle; and (ii) ipilimumab is intravenously administered to the subject on day -7, as well as cycle 1/day 15, cycle 2/day 8, and cycle 3/day 1. Additional induction doses of ipilimumab after cycle 3 are contemplated. In some embodiments, ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.002 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.02 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.06 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.2 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.6 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 1.8 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 5.4 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 10.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 15.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 20.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.002 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.02 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.06 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.2 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 0.6 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 1.8 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 5.4 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 10.0 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 15.0 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. In some embodiments, XmAb®23104 is intravenously administered at a dose of 20.0 mg/kg, and ipilimumab is intravenously administered at a dose of 1.0 mg/kg. A dministration

[00154] Antibodies of the methods provided herein can be administered by any method known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.

[00155] In a specific embodiment of the methods provided herein, the mode of administration is intravenous. In some embodiments, an antibody is administered by intravenous infusion or injection. In some embodiments, a CTLA-4 antibody (e.g., ipilimumab) is administered intravenously. In some embodiments of the various methods provided herein, XmAb®23104 is administered via intravenous infusion. In a specific embodiment, XmAb®23104 is administered via intravenous infusion at a constant rate over about a 1 hour period. Tn some embodiments, an ICOSxPD-1 antibody (e.g., XmAb®23104) is administered intravenously. In some embodiments of the various methods provided herein, ipilimumab is administered via intravenous infusion. In a specific embodiment, ipilimumab is administered via intravenous infusion at a constant rate over about a 90 minute period. In another specific embodiment, ipilimumab is administered at a dose of about 1 mg/kg via intravenous infusion at a constant rate over about a 90 minute period. In certain embodiments, a window between -5 minutes and +15 minutes is permitted.

[00156] In one embodiment, an ICOSxPD-1 antibody is administered intravenously. In one embodiment, an ICOSxPD-1 antibody is administered for about 35 to about 95 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 55 to about 75 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 35 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 40 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 45 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 50 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 55 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 60 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 65 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 70 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 75 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 80 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 85 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 90 minutes. In another embodiment, an ICOSxPD-1 antibody is administered for about 95 minutes. Tn another embodiment, an ICOSxPD-1 antibody is administered for about or at least about 1 hour. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104. [00157] In one embodiment of the methods provided herein comprising administration of an ICOSxPD-1 antibody and a CTLA-4 antibody, the CTLA-4 antibody is administered intravenously. In one embodiment, a CTLA-4 antibody is administered for about 65 minutes to about 125 minutes. In another embodiment, a CTLA-4 antibody is administered for about 85 minutes to about 105 minutes. In another embodiment, a CTLA-4 antibody is administered for about 65 minutes. In another embodiment, a CTLA-4 antibody is administered for about 70 minutes. In another embodiment, a CTLA-4 antibody is administered for about 75 minutes. In another embodiment, a CTLA-4 antibody is administered for about 80 minutes. In another embodiment, a CTLA-4 antibody is administered for about 85 minutes. In another embodiment, a CTLA-4 antibody is administered for about 90 minutes. In another embodiment, a CTLA-4 antibody is administered for about 95 minutes. In another embodiment, a CTLA-4 antibody is administered for about 100 minutes. In another embodiment, a CTLA-4 antibody is administered for about 105 minutes. In another embodiment, a CTLA-4 antibody is administered for about 110 minutes. In another embodiment, a CTLA-4 antibody is administered for about 115 minutes. In another embodiment, a CTLA-4 antibody is administered for about 120 minutes. In another embodiment, a CTLA-4 antibody is administered for about 125 minutes. In a specific embodiment of the methods provided herein, the ICOSxPD-1 antibody is XmAb®23104, and the CTLA-4 antibody is ipilimumab.

Additional Agents

[00158] In one aspect, provided is a method for treating a solid tumor in a subject, comprising administering to the subject an ICOSxPD-1 antibody alone or in combination with one or more additional agent(s).

[00159] Administration “in combination”, as used herein, means that two (z.e., an ICOSxPD-1 antibody of the disclosure and one additional agent), three (or more) different agents are administered to the subject for treating the same disease or disorder as the disease or disorder that the ICOSxPD-1 antibody of the disclosure is being used to treat in the subject (e.g, during the course of the subject’s affliction with the disorder, e.g., the two or more agents are administered after the human subject has been diagnosed with the tumor (e.g., solid tumor)). In some embodiments, the administration of one agent is still occurring when the administration of the second agent begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent administration”. In other embodiments, the administration of one agent ends before the administration of the other agent begins. In some embodiments of either case, the treatment is more effective because of combined administration. In some embodiments, administration is such that the reduction in a symptom, or other parameter related to the tumor is greater than what would be observed with one agent administered in the absence of the other. The effect of the agents on the subject can be partially additive, wholly additive, or greater than additive. The administration can be such that an effect of the first treatment administration is still detectable when the second is administered.

[00160] In some embodiments, an ICOSxPD-1 antibody is administered to a subject with at least one other or additional agent. In some embodiments, an ICOSxPD-1 antibody and a CTLA- 4 antibody is administered to a subject with at least one other or additional agent. The combination described herein and the at least one other agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the at least one other agent can be administered prior to or following administration of an ICOSxPD-1 antibody. In some embodiments, for sequential administration, the at least one other agent can be administered prior to or following administration of an ICOSxPD-1 antibody and/or a CTLA-4 antibody.

[00161] When administered in combination, the ICOSxPD-1 antibody and the at least one other agent, can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In some embodiments, the administered amount or dosage of the ICOSxPD-1 antibody and the at least one other agent, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the ICOSxPD-1 antibody and the at least one other agent, that results in a desired effect (e.g., treatment of tumor) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect.

[00162] In some embodiments, when administered in combination, the ICOSxPD-1 antibody, a CTLA-4 antibody, and the at least one other agent, can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In some embodiments, the administered amount or dosage of the ICOSxPD-1 antibody, a CTLA-4 antibody, and the at least one other agent, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the ICOSxPD-1 antibody, a CTLA-4 antibody, and the at least one other agent, that results in a desired effect (e.g, treatment of tumor) is lower (e.g, at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g, as a monotherapy, required to achieve the same therapeutic effect.

[00163] In one embodiment, administration in combination and/or monotherapy administration as disclosed herein can include a premedication with another agent. In some embodiments, the premedication is administered prior to administration of an ICOSxPD-1 antibody. In another embodiment, the premedication is administered prior to administration of an ICOSxPD-1 antibody and/or a CTLA-4 antibody.

[00164] In one embodiment, the premedication is a corticosteroid. In another embodiment, the premedication is dexamethasone. In another embodiment, the dexamethasone is administered intravenously at a dose of about 10 mg 1.5 hour (± 30 minutes) prior to administration of the ICOSxPD-1 antibody. In another embodiment, the dexamethasone is administered intravenously at a dose of about 10 mg 1.5 hour (± 30 minutes) prior to administration of a ICOSxPD-1 antibody and/or a CTLA-4 antibody.

[00165] In one embodiment, the premedication is diphenhydramine. In another embodiment, the diphenhydramine is administered intravenously at a dose of about 25 mg to about 50 mg, for example, 1.5 hour (± 30 minutes) prior to administration of an ICOSxPD-1 antibody. In another embodiment, the diphenhydramine is administered intravenously at a dose of about 25 mg to about 50 mg, for example, 1.5 hour (± 30 minutes) prior to administration of an ICOSxPD-1 antibody and/or a CTLA-4 antibody.

[00166] In another embodiment, the premedication is acetaminophen. In another embodiment, the acetaminophen is administered at a dose of 650 mg by mouth or intravenously 1.5 hour (± 30 minutes) prior to administration of an ICOSxPD-1 antibody. In another embodiment, the acetaminophen is administered at a dose of 650 mg by mouth or intravenously 1.5 hour (± 30 minutes) prior to administration of an ICOSxPD-1 antibody and/or a CTLA-4 antibody. [00167] In one aspect, administration in combination and/or monotherapy administration as disclosed herein can include administration of an agent to treat a side effect.

[00168] In one embodiment, the side effect is cytokine release syndrome (“CRS”). Symptoms of CRS may include high fevers, nausea, transient hypotension, hypoxia, and the like. CRS may include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthralgia, nausea, vomiting, and headache. CRS may include clinical skin signs and symptoms such as rash. CRS may include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. CRS may include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. CRS may include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potentially diminished cardiac output. CRS may include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. CRS may include clinical renal signs and symptoms such as azotemia. CRS may include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. CRS may include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, and seizures.

[00169] In another embodiment, the side effect is indigestion. In another embodiment, the side effect is nausea. In another embodiment, the side effect is vomiting. In another embodiment, the side effect is neurotoxicity. In another embodiment, the side effect is an allergic reaction, hypersensitivity, or an infusion-related reaction. In another embodiment, the side effect is hematologic toxicity. In another embodiment, the side effect is tumor lysis syndrome.

[00170] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of a steroid to a subject. In one embodiment, the steroid is a corticosteroid. In another embodiment, the corticosteroid is a glucocorticoid. In another embodiment, the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, prednisone, prednisolone, methylprednisolone, and triamcinolone. In another embodiment, the corticosteroid is selected from the group consisting of hydrocortisone, cortisone, and bethamethasone. In another embodiment, the steroid is fludrocortisone. In another embodiment, the steroid is dexamethasone.

[00171] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an antihistamine to a subject. In one embodiment, the antihistamine is an Hi antagonist. Tn another embodiment, the Hi antagonist is selected from the group consisting of acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelennamine, and triprolidine.

[00172] In an exemplary embodiment, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In another embodiment, the antihistamine is diphenhydramine. In another embodiment, the antihistamine is Benadryl®.

[00173] In an exemplary embodiment, the antihistamine is an Hi inverse agonist. In one embodiment, the Hi inverse agonist is selected from the group consisting of acrivastine, cetirizine, levocetirizine, desloratadine, and pyrilamine.

[00174] In an exemplary embodiment, the antihistamine is an H2 antihistamine. In one embodiment, the H2 antihistamine is an H2 antagonist. In another embodiment, the H2 antihistamine is an H2 inverse agonist. In another embodiment, the H2 antihistamine is selected from the group consisting of cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, and tiotidine.

[00175] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an antiallergy agent to a subject. In one embodiment, the other agent is selected from the group consisting of antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, antileukotriene agents, anticholinergics, and decongestants. In another embodiment, the other agent is a decongestant. In another embodiment, the other agent is an adrenaline releasing agent. In another embodiment, the other agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), or loratadine. In another embodiment, the other agent is an a-adrenergic receptor agonist. In another embodiment, the other agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetryzoline, tramazoline, or xylometazoline. [00176] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an antinausea agent to the subject. In one embodiment, the other agent is an antiemetic agent. In another embodiment, the other agent is a 5-HT3 receptor antagonist. In another embodiment, the other agent is a dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®), palonosetron (Aloxi®), mirtazapine (Remeron®). In another embodiment, the other agent is a dopamine antagonist. In another embodiment, the other agent is a 5-HT3 receptor antagonist. In another embodiment, the other agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®). In another embodiment, the other agent is a NK l receptor antagonist. In another embodiment, the other agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®). In an exemplary embodiment, the other agent is an anticholinergic. In another embodiment, the other agent is scopolamine.

[00177] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an analgesic agent. In one embodiment, the other agent is an antipyretic agent. In another embodiment, the other agent is a salicylate, or a derivative thereof. In another embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, and salicylic acid, or a derivative thereof. In another embodiment, the salicylate is selected from the group consisting of choline salicylate, magnesium salicylate, and sodium salicylate. In another embodiment, the other agent is aspirin. In another embodiment, the other agent is acetaminophen, or a derivative thereof. In another embodiment, the other agent is an NSAID, or a derivative thereof. In another embodiment, the NSAID is a propionic acid derivative. In another embodiment, the NSAID is selected from the group consisting of ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, or a derivative thereof. In another embodiment, the N SAID is ibuprofen. In another embodiment, the NSAID is naproxen. In another embodiment, the NSAID is an acetic acid derivative. In another embodiment, the NSAID is selected from the group consisting of indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, or a derivative thereof. In another embodiment, the NSAID is an enolic acid derivative. In another embodiment, the NSAID is selected from the group consisting of piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, or a derivative thereof. In another embodiment, the NSAID is an anthranilic acid derivative. In another embodiment, the NSAID is selected from the group consisting of mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, or a derivative thereof. In another embodiment, the other agent is selected from the group consisting of phenazone, metamizole, and nabumetone, or a derivative thereof. In another embodiment, the other agent is an opiate. In another embodiment, the other agent is codeine, morphine, thebaine, or fentanyl. In another embodiment, the other agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, or metopon.

[00178] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of a cytoprotective agent. In one embodiment, the other agent is an aminothiol compound. In another embodiment, the other agent is amifostine. In another embodiment, the other agent is bleomycin, dexrazoxane, or coenzyme M.

[00179] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of a vasopressor agent. In one embodiment, the vasopressor agent is selected from norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or a combination thereof. In another embodiment, the vasopressor agent is selected from dobutamine, midodrine, amezinium, or a combination thereof. [00180] In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an anticonvulsant agent. In one embodiment, the anticonvulsant is an aldehyde. In another embodiment, the aldehyde is paraldehyde. In another embodiment, the anticonvulsant is an aromatic allylic alcohol. In another embodiment, the aromatic allylic alcohol is stiripentol. In another embodiment, the anticonvulsant is a barbiturate. In another embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, or barbexaclone. In an exemplary embodiment, the anticonvulsant is a benzodiazepine. In another embodiment, the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, and nimetazepam. In another embodiment, the anticonvulsant is a carboxamide. In another embodiment, the carboxamide is carbamazepine, oxcarbazepine, or eslicarbazepine acetate. In an exemplary embodiment, the anticonvulsant is a fatty acid. In another embodiment, the fatty acid is a valproate. In another embodiment, the valproate is valproic acid, sodium valproate, or divalproex sodium. Tn another embodiment, the valproate is vigabatrin, progabide, and tiagabine. In another embodiment, the anticonvulsant is a fructose derivative. In another embodiment, the fructose derivative is topiramate. In another embodiment, the anticonvulsant is a GABA analog. In another embodiment, the GABA analog is gabapentin or pregabalin. In another embodiment, the anticonvulsant is a hydantoin. In another embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, or fosphenytoin. In another embodiment, the anticonvulsant is an oxazolidinedione. In another embodiment, the oxazolidinedione is paramethadione, trimethadione, and ethadione. In another embodiment, the anticonvulsant is a propionate. In another embodiment, the anticonvulsant is a pyrimidinedione. In another embodiment, the anticonvulsant is a pyrrolidine. In another embodiment, the pyrrolidine is brivaracetam, etiracetam, levetiracetam, or seletracetam. In another embodiment, the anticonvulsant is levetiracetam. In another embodiment, the anticonvulsant is a succinimide. In another embodiment, the succinimide is ethosuximide, phensuximide, mesuximide. In another embodiment, the anticonvulsant is a sulfonamide. In another embodiment, the succinimide is acetazolamide, sultiame, methazolamide, and zonisamide. In another embodiment, the anticonvulsant is a triazine. In another embodiment, the triazine is lamotrigine. In another embodiment, the anticonvulsant is a urea. In another embodiment, the urea is pheneturide or phenacemide. In another embodiment, the anticonvulsant is a valproylamide. In another embodiment, the anticonvulsant is a valproylamide. In another embodiment, the valproylamide is valpromide or valnoctamide. In another embodiment, the anticonvulsant is perampanel, stiripentol, or pyridoxine.

[001811 In an exemplary embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an agent that reduces an immune-mediated side effect. Exemplary immune-mediated side effects include, but are not limited to pneumonitis, colitis, hepatitis, nephritis and renal disfunction, hypothyroidism, hyperthyroidism, and endocrinopathies (e.g., hypophysitis, Type 1 diabetes mellitus and thyroid disorders such as hypothyroidism and hyperthyroidism). In one embodiment, the other agent reduces embryofetal toxicity.

[00182] In one embodiment, administration in combination and/or monotherapy administration as disclosed herein can include administration of an IV fluid. In another embodiment, the other agent is a bronchodilator. In another embodiment, the other agent is oxygen. Tn another embodiment, the other agent is tocilizumab. Tn another embodiment, the other agent is a proton pump inhibitor. In another embodiment, the other agent is a xanthine oxidase inhibitor. In another embodiment, the other agent is allopurinol. In another embodiment, the other agent is rasburicase.

Efficacy Assessments

[00183] Efficacy of the methods provided herein can be assessed by any method known in the art. For example, standard assays of efficacy can be run, such as cancer load, size of tumor, evaluation of presence or extent of metastasis, etc., immuno-oncology treatments can be assessed on the basis of immune status evaluations as well. This can be done in a number of ways, including both in vitro and in vivo assays. For example, changes in immune status, tumor burden, size, invasiveness, LN involvement, metastasis, etc. can be evaluated. In some embodiments, one or more improved efficacy endpoint(s) of a method of the disclosure is determined at least partially based on Response Evaluation Criteria in Solid Tumors (RECIST), Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST), and/or modified RECIST 1.1 for immune-based therapeutics (iRECIST). In some embodiments, one or more improved efficacy endpoint comprises higher percentage of objective response rate, best overall response, higher percentage of disease control rate, higher percentage of partial response, complete response, longer duration of response, longer progression-free survival, and/or longer overall survival.

[00184] In one embodiment, the efficacy is assessed by measuring the reduction in tumor size as compared to a reference. In one embodiment, the tumor size is reduced by about 10-100%. In another embodiment, the tumor size is reduced by about 10-30%. In another embodiment, the tumor size is reduced by about 40-60%. In another embodiment, the tumor size is reduced by about 70-100%. In another embodiment, the tumor size is reduced by about or at least about 10%. In another embodiment, the tumor size is reduced by about or at least about 20%. In another embodiment, the tumor size is reduced by about or at least about 30%. In another embodiment, the tumor size is reduced by about or at least about 40%. In another embodiment, the tumor size is reduced by about or at least about 50%. In another embodiment, the tumor size is reduced by about or at least about 60%. In another embodiment, the tumor size is reduced by about or at least about 70%. In another embodiment, the tumor size is reduced by about or at least about 80%. In another embodiment, the tumor size is reduced by about or at least about 90%. In another embodiment, the tumor size is reduced by about 100%. Tn some embodiments, the size of the tumor is reduced by about or at least about 10%, about or at least about 20%, about or at least about 30%, about or at least about 40%, about or at least about 50%, about or at least about 60%, about or at least about 70%, about or at least about 80%, about or at least about 90%, or about 100%. In some embodiments, the size of the tumor in a subject is reduced after an ICOSxPD-1 antibody is administered to the subject as compared to a reference. In some embodiments, the size of the tumor in a subject is reduced after an ICOSxPD-1 antibody and a CTLA-4 antibody is administered to the subject as compared to a reference. In some embodiments, the reference is the size of the tumor prior to the administration of an ICOSxPD-1 antibody to a subject. In some embodiments, the reference is the size of the tumor prior to the administration of an ICOSxPD-1 antibody and/or a CTLA-4 antibody to a subject. In some embodiments, the reference is the size of the tumor in another subject or in a population of subjects. In some embodiments, the another subject or the population of subjects have the same solid tumor (e.g, same type and/or same cancer stage grouping) as the subject.

[00185] In an exemplary embodiment, the efficacy is measured by a decrease in the number of cancer cells in a biological sample obtained from the subject as compared to a reference. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point. In another embodiment, the reference is a predetermined value. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from another subject with a solid tumor. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from a population of subjects with solid tumors. In an embodiment, the biological sample is blood. In another embodiment, the biological sample is serum. In another embodiment, the biological sample is plasma. In some embodiments, the biological sample is a biopsy from a solid tumor.

[00186] In an exemplary embodiment, efficacy is assessed by evaluating the absolute count and percentage change from baseline for a cell population. In one embodiment, the cell population is B cells. In another embodiment, the cell population is T cells. In another embodiment, the cell population is natural killer (NK) cells.

[00187] In an exemplary embodiment, efficacy is assessed by evaluating changes in gene expression or protein levels of diagnostic biomarkers including, but not limited to, the biomarkers in Table 7. In one embodiment, expression of one or more genes is increased following treatment with the methods provided herein. Tn another embodiment, expression of one or more genes is decreased following treatment with the methods provided herein. In one embodiment, the level of one or more proteins is increased following treatment with the methods provided herein. In another embodiment, the level of one or more proteins is decreased following treatment with the methods provided herein.

[00188] In one embodiment, efficacy is assessed by evaluating peripheral and intratumoral leukocyte frequencies, phenotypes, and functional and activation markers at baseline and following treatment.

[00189] In an exemplary embodiment, efficacy is assessed using gene expression profiling for cell of origin subtyping and exploratory transcriptomic analysis. In another embodiment, efficacy is assessed by genomic analysis in the tumor, including, but not limited to, FcR genotyping, and MRD ctDNA analysis in blood.

[00190] In some embodiments, assessment of treatment is done by assessing T cell activity measured by cytokine production, measure either intracellularly in culture supernatant using cytokines including, but not limited to, IFNy, TNFa, GM-CSF, IL2, IL6, IL4, IL5, IL 10, IL 13 using well known techniques. It is observed that the dosages provided herein advantageously elicit only a limited low rate and grade cytokine release syndrome (CRS) response in some subjects. In some embodiments, the dosages provided herein elicit at most a Grade 1 or Grade 2 CRS response. See Lee et al., Blood 124(2): 188-195 (2014) and Porter et al., J. Hematol Oncol. 11( 1 ):35 (2018), which are incorporated by reference in pertinent parts relating to CRS grading systems. In some embodiments, the dosages provided herein advantageously elicit reduced levels of a CRS-associated cytokine in subsequently dosages. In some embodiments, the dosages provided herein advantageously elicit reduced levels of a CRS-associated cytokine after two dosages. In certain embodiments, the CRS-associated cytokine is IL-6 and/or interferon y. Cytokine levels can be measured by any suitable method such as, for example, ELISA assay methods.

[00191] In an exemplary embodiment, efficacy is assessed by evaluating progression-free survival. In one embodiment, a subject treated using the methods provided herein has an increase in progression-free survival. Progression-free survival can be assessed as compared to a reference. In some embodiments, the reference is a subject prior to receiving a treatment provided herein. In some embodiments, the reference is a subject that has not received a treatment provided herein. Tn some embodiments, the reference is the subject’s baseline progression before receiving a treatment provided herein. In an embodiment, progression-free survival is increased by about or at least about one month. In another embodiment, progression- free survival is increased by about or at least about two months. In another embodiment, progression-free survival is increased by about or at least about three months. In another embodiment, progression-free survival is increased by about or at least about four months. In another embodiment, progression-free survival is increased by about or at least about five months. In another embodiment, progression-free survival is increased by about or at least about six months. In another embodiment, progression-free survival is increased by about or at least about seven months. In another embodiment, progression-free survival is increased by about or at least about eight months. In another embodiment, progression-free survival is increased by about or at least about nine months. In another embodiment, progression-free survival is increased by about or at least about ten months. In another embodiment, progression-free survival is increased by about or at least about eleven months. In another embodiment, progression-free survival is increased by about or at least about one year. In another embodiment, progression-free survival is increased by about or at least about two years. In another embodiment, progression-free survival is increased by about or at least about three years. In another embodiment, progression-free survival is increased by about or at least about four years. In another embodiment, progression-free survival is increased by about or at least about five years. In another embodiment, progression-free survival is increased by more than about five years.

[001921 Iⁿ an exemplary embodiment, efficacy is assessed by evaluating overall survival. In one embodiment, a subject treated using the methods provided herein has an increase overall survival. Overall survival can be assessed as compared to a reference. In some embodiments, the reference is a subject that has not received a treatment provided herein. In an embodiment, overall survival is increased by about or at least about one month. In another embodiment, overall survival is increased by about or at least about two months. In another embodiment, overall survival is increased by about or at least about three months. In another embodiment overall survival is increased by about or at least about four months. In another embodiment, overall survival is increased by about or at least about five months. In another embodiment, overall survival is increased by about or at least about six months. In another embodiment, overall survival is increased by about or at least about seven months. Tn another embodiment, overall survival is increased by about or at least about eight months. In another embodiment, overall survival is increased by about or at least about nine months. In another embodiment, overall survival is increased by about or at least about ten months. In another embodiment, overall survival is increased by about or at least about eleven months. In another embodiment, overall survival is increased by about or at least about one year. In another embodiment, overall survival is increased by about or at least about two years. In another embodiment, overall survival is increased by about or at least about three years. In another embodiment, overall survival is increased by about or at least about four years. In another embodiment, overall survival is increased by about or at least about five years. In another embodiment, overall survival is increased by more than about five years.

[00193] In an exemplary embodiment, efficacy is assessed by evaluating objective response rate. In one embodiment, subjects treated with the methods provided herein have an objective response rate of about 10% to about 100%. On embodiment, the objective response rate is about or at least about 10%. In another embodiment, the objective response rate is about or at least about 20%. In another embodiment, the objective response rate is about or at least about 30%. In another embodiment, the objective response rate is about or at least about 40%. In another embodiment, the objective response rate is about or at least about 50%. In another embodiment, the objective response rate is about or at least about 60%. In another embodiment, the objective response rate is about or at least about 70%. In another embodiment, the objective response rate is about or at least about 80%. In another embodiment, the objective response rate is about or at least about 90%. In another embodiment, the objective response rate is about 100%.

[00194] In an exemplary embodiment, efficacy is assessed by evaluating time to treatment failure. In one embodiment, a subject treated using the methods provided herein has an increase in time to treatment failure.

[00195] In an exemplary embodiment, efficacy is assessed by evaluating duration of response. In one embodiment, a subject treated using the methods provided herein has an increased duration of response. In some embodiments, a subject treated using the methods provided herein reaches remission. In some embodiments, a subject treated using the methods provided herein achieves complete response. 5. EXAMPLES

[00196] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation.

EXAMPLE 1 - Treatment of advanced tumors using an ICOSxPD-1 antibody administered with or without ipilimumab

[00197] A phase 1, first-in-human (FIH), multiple-dose study is conducted to evaluate the safety and tolerability of an ICOSxPD-1 antibody of the disclosure administered with or without a CTLA-4 antibody (e.g., ipilimumab) in subjects with selected advanced solid tumors. The study is conducted in two parts: Part A is the dose-escalation phase of the study and Part B is the cohort expansion phase of the study.

[00198] The ICOSxPD-1 antibody is a humanized bispecific antibody that binds the immune checkpoint molecule PD-1 and the costimulatory molecule ICOS. While an ICOSxPD-1 antibody is expected to preferentially bind cells that simultaneously express ICOS and PD-1, the anti-ICOS arm is believed to have immune agonist activity.

[00199] CTLA4 blockade has been shown to induce expansion of 1COS+ effector T cells in prostate cancer, bladder cancer, melanoma, and hepatocellular cancer (Chen et al. Proc Natl Acad Sci USA. 2009;106(8):2729-34; Liakou et al. Proc Natl Acad Sci USA. 2008; 105(39): 14987-92; Agdashian etal. Cancer Immunol Immunother. 2019;68(4):599-608; Wei et al. Cell. 2017; 170(6): 112033. el 117.). A retrospective analysis of a small melanoma study showed that an increase of ICOS+ T cells correlated to increased likelihood of clinical benefit (Carthon et al.

Clin Can Res;2010;16(10):2861-71.). Based on these data, in addition to ICOSxPD-1 antibody treatment, the Part B expansion explores CTLA4 blockade using ICOSxPD-1 antibody in combination with CTLA-4 antibody (e.g., ipilimumab).

5.1 Treatment Regimens

[00200] This study consists of 2 parts:

[00201] Part A: Dose-Escalation Phase

[00202] Part B: Expansion Phase

[00203] Part A : Dose-Escalation Phase

[00204] Part A is designed to define a maximum tolerated dose and/or recommended dose (MTD/RD) of an ICOSxPD-1 antibody. In Part A, an accelerated titration dose escalation scheme is used for the first 2 dose cohorts, followed by standard 3 + 3 dose escalation for the remaining cohorts. The initial dose level in Part A is 0.002 mg/kg, and subsequent dose levels (if reached) are 0.02, 0.06, 0.2, 0.6, 1.8, 5.4, 10, 15 and 20 mg/kg with the potential to continue to escalate beyond dose level 10, if the safety profile allows, and each higher dose level representing a < 50% increase above the immediate prior dose level. The initial treatment period for each subject in this study is 2 cycles. Subjects receive infusions of an ICOSxPD-1 antibody on Days 1 and 15 of each 28-day cycle.

[00205] Part A contains 2 parallel dose-escalation groups based on the subject’s prior pembrolizumab exposure (pembrolizumab was found to interfere with an ICOSxPD-1 antibody binding in a competitive fashion in vitro). Subjects who are either naive to treatment with pembrolizumab or have received pembrolizumab > 24 weeks prior to study enrollment are enrolled sequentially in up to 10 dose-level cohorts (Cohorts 1A-10A), with the potential to continue to escalate beyond dose level 10, if the safety profde allows, and each higher dose level representing a < 50% increase above the immediate prior dose level. Subjects who have received pembrolizumab > 6 weeks and < 24 weeks prior to enrollment are enrolled sequentially in up to 8 dose-level cohorts (Cohorts 3B-10B) beginning at the third dose level (0.06 mg/kg). Subjects who are either naive to treatment with pembrolizumab or have received pembrolizumab > 24 weeks prior to study enrollment are enrolled sequentially in 10 planned dose-level cohorts (Cohorts 1A-10A), with the potential to continue to escalate beyond dose level 10, if the safety profde allows, and each higher dose level representing a < 50% increase above the immediate prior dose level. Subjects who have received nivolumab > 4 weeks prior to enrollment are enrolled sequentially in Cohorts 1A-10A. Enrollment into Cohort 3B begins if and when the first 2 dose-level cohorts (Cohorts 1A and 2A) have cleared safety evaluation by the Dose-Escalation Review Committee (DERC). The B cohorts in Part A continue to escalate in parallel to the A cohorts unless a decision is made by the sponsor and/or DERC that the data being collected in the B cohorts is no longer informative.

[00206] A minimum of 1 subject is enrolled in each dose-escalation cohort during the accelerated titration phase of dose escalation (Cohorts 1 A and 2A), and a minimum of 3 subjects are enrolled during the standard 3 + 3 dose-escalation phase (Cohorts 3 and higher).

[00207] In Part A, the first subject is dosed and observed for a minimum of 24 hours before study drug is administered to the remainder of the cohort; no 2 subjects within a cohort start treatment with an TCOSxPD-1 antibody on the same day. All subjects are assessed for the development of dose limiting toxicides (DLTs) during treatment with an ICOSxPD-1 antibody. The DLT assessment period is defined as Cycle 1, Days 1 through 28.

[00208] Part B: Expansion Phase

[00209] Part B, the cohort expansion phase of the study, enrolls study subjects at the MTD/RD determined in Part A and enrolls up to 150 subjects (safety lead-in N=6 plus diseasespecific cohorts N=144) with select advanced tumors into disease-specific expansion groups: undifferentiated pleomorphic sarcoma (UPS), including other select high-grade soft-tissue sarcomas (STS) such as myxofibrosarcoma (MFS); non-squamous non-small cell lung carcinoma (NSCLC); head and neck squamous cell carcinoma (HNSCC), including nasopharyngeal carcinoma (NPC); colorectal cancer (CRC); renal cell carcinoma, clear cell histology (ccRCC); and melanoma. These tumor types were chosen based on high ICOS expression in tumor infiltrating lymphocytes and clinical response in the escalation phase of the study.

[00210] There is a safety lead-in cohort for subjects receiving an ICOSxPD-1 antibody in combination with ipilimumab with 6 subjects, from the list of Part B expansion disease groups. The phase 2 dose of an ICOSxPD-1 antibody was determined to be 10 mg/kg based on tolerability, clinical responses, pharmacodynamic data and investigator input. These subjects in the safety lead-in receive 10 mg/kg of an ICOSxPD-1 antibody and 1 mg/kg of ipilimumab. If < 1 dose limiting toxicity (DLT) has occurred in 6 subjects, the expansion disease-specific cohorts initiate at the RD determined in Part A. Expansion phase enrolls 6 disease-specific cohorts: UPS, NSCLC, HNSCC, CRC, ccRCC and melanoma. For each tumor type cohort, the study is conducted in two stages. Stage 1 assigns 12 subjects to each of the tumor type cohorts; 6 randomized to receive an ICOSxPD-1 antibody and 6 randomized to receive an ICOSxPD-1 antibody in combination with ipilimumab. Once 12 subjects have been randomized at Stage 1 in each disease-specific cohort, there is an enrollment hiatus to allow for the subjects to be followed through 2 cycles to the first response assessment. Subject replacements may be needed for subjects that do not have evaluable post-baseline response assessments. Subjects who discontinue treatment due to related adverse events (AEs), death or clinical progression without an evaluable post-baseline assessment may not be replaced. An interim analysis is performed on the efficacy response data at the end of Stage 1 when 12 subjects have either withdrawn/not replaced or have been followed to the first response assessment. [00211] Based on the results of the interim analysis for Stage 1 of each cohort, and review of safety data in consultation with the DERC, a decision is made whether or not to proceed to Stage 2. If yes, Stage 2 continues to randomize an additional 12 subjects, 6 to receive an ICOSxPD-1 antibody and 6 to receive an ICOSxPD-1 antibody in combination with ipilimumab. The study flow chart is provided in FIG. 2. All subjects are assessed for the development of DLTs during treatment with an ICOSxPD-1 antibody. The DLT assessment period is defined as Cycle 1, Days 1 through 28.

[00212] A DLT is defined as any adverse event (AE) or clinically significant abnormal laboratory value (unless clearly attributable to underlying malignancy or concomitant disease) occurring during Cycle 1 through Day 28 and meeting one of the following criteria.

[00213] Non-hematologic Toxicity:

• Any Grade > 4 toxicity

• Any Grade 3 toxicity lasting > 3 days despite optimal supportive care, except for the following:

- Grade 3 rash that resolves to < Grade 2 in < 7 days with therapy

- Grade 3 arthralgia that resolves to < Grade 2 in < 7 days or can be managed with optimal supportive care

- Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be managed by endocrine therapy that does not include systemic corticosteroids

- Grade 3 tumor flare (defined as local pain, irritation, or rash localized to site of suspected tumor) that resolves to < Grade 2 in < 7 days

• Grade 3 elevation of serum hepatic transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) lasting > 7 days

• Any increase in hepatic transaminase (ALT or AST) > 3 x baseline in combination with either an increase in direct bilirubin > 2 x upper limit of normal (ULN) or clinical jaundice, in the absence of cholestasis or other contributory factors Any Grade 3 laboratory value that persists for > 1 week or that requires medical intervention or hospitalization, except for the following:

- Isolated Grade 3 lipase values that are not accompanied by Grade > 3 amylase values or clinical

- symptoms or radiographic evidence of pancreatitis

- Grade > 3 lymphopenia, which is an expected pharmacologic effect of immunotherapy

• Any immune-related adverse event (irAE) that requires permanent discontinuation of study drug according to the management guidelines set forth in the National Comprehensive Cancer Network (NCCN) Guidelines - Management of Immunotherapy - Related Toxi cities

[00214] Hematologic Toxicity:

• Any Grade > 4 toxicity, except for the following:

- Grade 4 neutropenia lasting < 7 days is not considered a DLT.

- Grade 4 thrombocytopenia < 7 days and not associated with clinically significant bleeding is not considered a DLT.

• Any irAE that requires permanent discontinuation of study drug

[00215] If a subject does not complete the DLT period (including both doses of study drug) for reasons other than toxicity or is not assessable for toxicity throughout the period, the subject is replaced. Dose escalation in Part A proceeds according to the Dose-Escalation Scheme, and the final decision to escalate to a higher dose level is made by a DERC based on review of the aggregate safety data for all subjects through Cycle 1 Day 28. Data about toxi cities occurring outside the DLT period including late toxicities, are collected, analyzed, and presented for consideration by the DERC in determining the safety and tolerability of a dose. The DERC can make adaptations to the dosing schema if necessary, in accordance with evolving trial safety and tolerability findings, as long as changes do not significantly affect the risk profile of the study. [002161 Primary Objectives: 1) to evaluate the safety and tolerability of an ICOSxPD-1 antibody with and without ipilimumab in subjects with selected advanced solid tumors that have progressed after treatment with standard/approved therapies or have no appropriate available therapies; and 2) to identify the maximum tolerated dose (MTD) and/or recommended dose (RD)/schedule for an ICOSxPD-1 antibody administered by intravenous (IV) dosing on Days 1 and 15 of each 28-day cycle in subjects with selected advanced solid tumors.

[00217] Secondary Objectives: 1) to characterize the pharmacokinetics (PK) and immunogenicity of an ICOSxPD-1 antibody with and without ipilimumab; and 2) to assess preliminary anti -tumor activity of an ICOSxPD-1 antibody with and without ipilimumab by objective response rates (ORR), duration of response (DOR), and best overall response rates (BOR), per response evaluation criteria outlined in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and by progression-free survival (PFS).

[00218] Exploratory Objectives: 1) to assess preliminary anti-tumor activity of an ICOSxPD- 1 antibody administered as a monotherapy and in combination with ipilimumab by ORR and BOR rates, PFS, and DOR, per response evaluation criteria outlined in the following: - Immune- modified RECIST (imRECIST) - Modified RECIST 1.1 for immune-based therapeutics (iRECIST); 2) to characterize pharmacodynamics of inflammatory indices in the peripheral blood by measuring receptor occupancy and soluble and cellular markers of activation/proliferation of peripheral T-cell subsets before and after administration of an ICOSxPD-1 antibody as a monotherapy and in combination with ipilimumab; 3) to characterize pharmacodynamics of inflammatory indices in the tumor microenvironment (TME) by immunohistological analysis of the cellular composition of the tumor immune infiltrate and the expression of inflammatory modulators that may include inducible cytotoxic T lymphocyte antigen 4 (CTLA4), costimulator (ICOS), programmed cell death ligand 1 (PDL1) and programmed cell death protein 1 (PD1) of both archival tumor tissue and fresh tumor biopsies before and after an ICOSxPD-1 antibody administration as a monotherapy and in combination with ipilimumab administration; 4) to characterize pharmacodynamics of inflammatory transcriptional signatures of the tumor microenvironment (TME) by analysis of archival tumor tissue and fresh tumor biopsies (if available) before and after administration of an ICOSxPD-1 antibody administered as a monotherapy and in combination with ipilimumab administration; and 5) to correlate clinical response with tumor mutational burden, immune cell infdtration, expression of soluble or cellular immunomodulatory markers and inflammatory transcriptional signatures as assessed in archival tumor tissue and/or fresh tumor biopsies (if available).

[00219] Treatment Plan

[00220] Subjects are given an ICOSxPD-1 antibody intravenously on Days 1 and 15 of each 28-day cycle, for a total of 2 cycles. Subjects are allowed to continue to receive an ICOSxPD-1 antibody beyond 2 cycles, if they meet specified criteria or if, the subject is deriving benefit from the therapy. In the expansion phase of the study (Part B), the treatment period for each subject on ipilimumab is 2 cycles. Each cycle is 28 days long, with each ipilimumab dose occurring once every 3 weeks. Three induction doses of ipilimumab are planned in 2 cycles, but up to 4 total induction doses of ipilimumab are allowed should the subject continue treatment beyond 2 cycles. An ICOSxPD-1 antibody is administered by IV infusion at a constant rate over 1 hour. Ipilimumab is administered at a dose of 1 mg/kg over a 90-minute IV infusion. On days when both ipilimumab and an ICOSxPD-1 antibody are administered, ipilimumab is given first; an ICOSxPD-1 antibody is started 60 minutes after the end of the ipilimumab infusion. For each cohort in Part A, the first subject is dosed and observed for a minimum of 24 hours before study drug is administered to the remainder of the cohort; no 2 subjects within a cohort start treatment with an ICOSxPD-1 antibody on the same day. At the end of Cycle 2 and every second cycle thereafter for subjects who continue to receive an ICOSxPD-1 antibody, the subject undergoes a tumor response assessment.

[00221] Primary Endpoints.

[00222] The primary endpoint of the study is safety, as measured by incidence of treatment- emergent AEs (TEAEs), clinically significant changes in safety laboratory tests, physical examination (PE) findings, vital signs, electrocardiogram (ECG), and DLTs used to determine the MTD and/or RD and schedule of an ICOSxPD-1 antibody administered with and without ipilimumab for evaluation in future studies.

[00223] Secondary Endpoints.

[00224] The secondary endpoints of the study includes: characterizing PK based on the parameters of Cmax, time to reach maximum concentration (tmax), ti/2, AUCo-oc, CL, Vd, AUC from time zero to the time point of the last measurable concentration (AUCiast), AUC from time zero to the end of the dosing interval, tau (AUCtau), and terminal k_e; assessing immunogenicity by incidence of antibodies directed to an ICOSxPD-1 antibody and qualitative assessment of safety outcomes; evaluating preliminary anti-tumor activity of an ICOSxPD-1 antibody administered with and without ipilimumab by RECIST 1.1 assessment as well as aggregate data for all subjects for objective response rates (ORR), best overall response rates (BOR), progression-free survival (PFS), and duration of response (DOR).

[00225] Exploratory Endpoints.

[00226] The exploratory endpoints of the study includes: preliminary anti-tumor activity of an ICOSxPD-1 antibody administered as a monotherapy and in combination with ipilimumab by imRECIST and iRECIST: ORR, BOR rates, PFS, and DOR; changes in peripheral markers of immune cell activation as assessed by quantification of inflammatory soluble mediators and flow cytometric analysis of receptor occupancy and T-cell proliferation/activation following an ICOSxPD-1 antibody administered as a monotherapy and in combination with ipilimumab administration; changes in the tumor microenvironment (TME) of immune cell activation as assessed by immunohistological analysis of the cellular composition of the tumor infiltrate and the cellular expression of immunomodulators that may include ICOS, CTLA4, PDL1 and PD1 of both archival tumor tissue and fresh tumor biopsies before and after an ICOSxPD-1 antibody is administered as a monotherapy and in combination with ipilimumab administration; changes in the TME of immune cell activation as assessed by inflammatory transcriptional signatures before and after an ICOSxPD-1 antibody is administered as a monotherapy and in combination with ipilimumab administration; correlation between immunohistological intratumoral immune cell infiltrates and clinical response; correlation between immunohistological expression of immunomodulators CTLA4, PDL1, PD1, and ICOS and clinical response; and correlation between inflammatory transcriptional signatures and clinical response.

5.2 Number of Subjects

[00227] The study enrolls up to 258 subjects into both Parts A and B.

[00228] Part A enrolls up to 108 subjects with a minimum of 1 subject in each dose-escalation cohort during the accelerated titration phase of dose escalation (Cohorts 1 A and 2A), and a minimum of 3 subjects are enrolled during the standard 3 + 3 dose-escalation phase (Cohorts 3 and higher). [00229] Part B enrolls up to 150 subjects with select advanced tumors into disease-specific expansion groups: undifferentiated pleomorphic sarcoma (UPS), including other select highgrade soft-tissue sarcomas (STS) such as myxofibrosarcoma (MFS); non-squamous non-small cell lung carcinoma (NSCLC); head and neck squamous cell carcinomas (HNSCC) including nasopharyngeal carcinoma (NPC); colorectal cancer (CRC); ccRCC, and melanoma. There is a safety lead-in cohort for subjects receiving an ICOSxPD-1 antibody in combination with ipilimumab with 6 subjects. The expansion phase is conducted in two stages. Stage 1 assigns 12 subjects to each of the tumor type cohort; 6 randomized to receive an ICOSxPD-1 antibody and 6 randomized to receive an ICOSxPD-1 antibody in combination with ipilimumab. Based on the results of the interim analysis for Stage 1 of each cohort, and review of safety data in consultation with the DERC, a decision is made whether or not to proceed to Stage 2. If a decision is made to proceed with Stage 2, Stage 2 continues to randomize an additional 12 subjects, 6 to receive an ICOSxPD-1 antibody and 6 to receive an ICOSxPD-1 antibody in combination with ipilimumab.

5.3 Treatment Assignment

[00230] Subjects who consent for the study are assigned a Subject Screening Number. Subjects eligible to receive study treatment are assigned a Subject Enrollment Number.

[00231] Part A: Dose-Escalation Study

[00232] During Part A, enrolled subjects are assigned to an open-dose cohort. No more than 1 subject is initiated on treatment with an ICOSxPD-1 antibody on any given day during the MTD and/or RD determination phase.

[00233] Part B: Expansion Study

[00234] In each of the two stages of Expansion (Part B), subjects are randomly assigned to monotherapy or combination therapy in a 1 : 1 ratio within each of 6 tumor type cohorts (UPS, NSCLC, HNSCC, CRC, ccRCC and melanoma) based on a pre-generated permuted-block randomization list.

[00235] The randomization is open-label (unblinded) due to the different dosing schedules between monotherapy and combination therapy and any analyses that make direct comparisons between the efficacy of monotherapy and of the combination are considered exploratory.

5.4 Subject Inclusion Criteria

[00236] Subjects selected for the study are at least 18 years of age. [00237] For enrollment in Part A, subjects must have a diagnosis of histologically or cytologically confirmed advanced solid tumors, including the following: melanoma (excluding uveal melanoma); cervical carcinoma; pancreatic carcinoma; breast carcinoma that is estrogen receptor, progesterone receptor, and Her2 negative; hepatocellular carcinoma; urothelial carcinoma; HNSCC; NPC; renal cell carcinoma; colorectal cancer; endometrial carcinoma; NSCLC; small cell lung cancer; gastric or gastroesophageal junction adenocarcinoma; and sarcoma.

[00238] For enrollment in Part B, subjects must have a diagnosis of histologically or cytologically confirmed advanced solid tumors of the following types: non-squamous NSCLC; melanoma; HNSCC, including NPC; CRC; UPS, including other select high-grade STS, such as MFS; and ccRCC.

[00239] Prior to enrolling Part B (expansion), subjects should have received disease-specific standard therapy as indicated here:

[00240] a. Non-squamous NSCLC: i. Subjects whose tumors are EGFR, ALK, ROS1, BRAF negative or unknown and PDL1 < 50% or unknown: cisplatin-based or carboplatin-based chemotherapy ii. Subjects whose tumors have an EGFR sensitizing mutation: first-line therapy with afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib iii. Subjects whose tumors have an ALK rearrangement: first-line therapy with alectinib, brigatinib, ceritinib, crizotinib, or lorlatinib iv. Subjects whose tumors have a ROS1 rearrangement: first-line therapy with entrectinib, ceritinib, or crizotinib v. Subjects whose tumors have a BRAF V600E mutation: first-line therapy with dabrafenib ± trametinib vi. Subjects whose tumors have PDL1 > 50%: first-line therapy with the following: pembrolizumab, pembrolizumab/carboplatin/pemetrexed, pembrolizumab/cisplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab or cemiplimab-rwlc vii. Subjects have life expectancy > 3 months b. Melanoma i. Subjects with metastatic or unresectable disease have been treated with anti- PD 1 monotherapy, including nivolumab or pembrolizumab ii. Subjects with BRAF V600-activating mutation have been treated with combination therapy including dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib iii. Subjects have life expectancy > 3 months c. HNSCC, including NPC: i. Subjects with recurrent, unresectable, or metastatic disease have received platinum-containing combination chemotherapy ii. Subjects have received cetuximab with or without either pembrolizumab or nivolumab for platinum-resistant disease. Subjects may be considered if they have declined cetuximab (e.g, for anaphylaxis risk) iii. NPC: Subjects have received platinum-based chemotherapy regimen either in combination with radiation or in a palliative setting iv. Subjects have life expectancy > 3 months d. CRC: i. Subjects appropriate for intensive therapy have received a FOLFOX/CAPEOX/FOLFIRI ± bevacizumab ii. Subjects not appropriate for intensive therapy have received 5 FU+leucovorin ± bevacizumab or capecitabine ± bevacizumab iii. Subjects have life expectancy > 3 months e. UPS, including other select high-grade STS such as MFS: i. Subjects have received at least 1 prior systemic therapy ii. Subjects have life expectancy > 3 months f. RCC, clear cell histology (ccRCC) i. Subjects must have received either a tyrosine kinase inhibitor with or without an anti PD- 1 or PDL- 1 therapy or ipilimumab + nivolumab ii. Subjects have life expectancy > 3 months.

[00241] All subjects’ cancer must have progressed after treatment with standard/approved therapies or have no appropriate available therapies. Subjects must have measurable disease by RECIST 1.1. All subjects must have adequate archival tumor sample (slides or archival formalin- fixed paraffinized embedded (FFPE) blockfs] containing tumor). A fresh tumor sample satisfies this criterion for those subjects who do not have adequate archival tumor sample. For subjects in Part A, this means a fresh screening tumor biopsy becomes mandatory.

[00242] All subjects in Part B (dose expansion) must have a tumor lesion that can be biopsied at acceptable risk and must agree to both a fresh biopsy during screening and a second biopsy to be collected between Day 21-28 of Cycle 1. For subjects in Part A (dose escalation), the fresh biopsies should also be collected (though these are not required for participation in the study, unless a screening biopsy is needed in lieu of archival tumor sample, in which case the screening biopsy then becomes mandatory for participation). Subjects have an Eastern Cooperative Oncology Group performance status of 0-1. Female subjects of childbearing potential must agree to use a highly effective method of birth control during and for 4 weeks after the last dose of an ICOSxPD-1 antibody if they receive an ICOSxPD-1 antibody monotherapy or for 12 weeks (90 days) after the last dose of ipilimumab.

[00243] Diagnosis and Main Criteria for Exclusion: subjects who meet any of the following criteria are excluded from the study

1. Subjects currently receiving other anti cancer therapies

2. Prior treatment with an investigational anti-ICOS therapy

3. Treatment with any programmed cell death ligand- 1 or -2 (PDL1 or PDL2)-directed therapy within 4 weeks of the start of study drug

4. Treatment with nivolumab within 4 weeks of the start of study drug

5. Treatment with pembrolizumab within 24 weeks of the start of study drug for Cohorts 1A through 10A

6. Subjects who have had pembrolizumab < 6 weeks of the start of study drug are ineligible for this study

7. Treatment with any other anticancer therapy within 2 weeks of the start of study drug (e.g, other immunotherapy, chemotherapy, radiation therapy, etc.).

8. A life-threatening (Grade 4) irAE related to prior immunotherapy

9. Failure to recover from any irAE from prior cancer therapy to Grade < 1, except for endocrinopathies that are on stable hormone replacement doses

10. Failure to recover from any other toxicity (other than immune-related toxicity) related to previous anticancer treatment to Grade < 2 1 1. Known active central nervous system involvement by malignant disease. Subjects with previously treated brain metastases may participate provided they are radiologically stable, /'.e., are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening) and are clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

12. Platelet count < 100 * 10⁹/L

13. Hemoglobin level < 8.5 g/dL

14. Absolute neutrophil count < 1.0 * 10⁹/L

15. AST at screening > 3 * ULN for subjects without known liver involvement by tumor; or > 5 x ULN for subj ects with known liver involvement by tumor

16. ALT at screening > 3 * ULN for subjects without known liver involvement by tumor; or > 5 x ULN for subj ects with known liver involvement by tumor

17. Bilirubin > 1.5 x ULN (unless prior diagnosis and documentation of ongoing hemolysis or Gilbert’s syndrome has been made)

18. Estimated creatinine clearance (CL) < 30 mL/min calculated by the Cockcroft-Gault or modification of diet in renal disease formulas

19. Active known or suspected autoimmune disease (except that subjects are permitted to enroll if they have vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and non-steroidal anti-inflammatory drugs)

20. Have any condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of study drug (except that inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response are permitted)

21. Receipt of an organ allograft

22. History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, renal, metabolic, hematologic, or psychiatric) other than their primary malignancy, that would pose a risk to subject safety or interfere with study evaluations, procedures, or completion 23. Evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of study drug

24. Treatment with antibiotics within 14 days prior to first dose of study drug

25. Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

26. Positive test for HIV antibodies or antigen.

27. Known active hepatitis infection: a. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis core antibody (HBcAb; a subject whose HBsAg or HBcAb is positive may be enrolled if an HBV DNA test is negative and either the subject is treated with potent antiviral therapy or is re-tested for HBV DNA every month) b. Positive test for hepatitis C virus (HCV) antibodies (a subject whose HCV antibody test is positive may be enrolled if quantitative HCV polymerase chain reaction test is negative)

28. Subject is pregnant or breast feeding, or planning to become pregnant while enrolled in the study, up to the final end of treatment visit

29. Positive urine pregnancy test (ie, urine human chorionic gonadotropin)

30. Treatment with ipilimumab within 4 weeks of the start of study drug

31. Known hypersensitivity to ipilimumab or to any ingredient in the formulation or component of the container

5.5 Dosing Schedule

[00244] The treatment period for each subject in this study is 2 cycles. Each cycle is 28 days long and consists of 2 doses of an ICOSxPD-1 antibody, on Days 1 and 15. In Part A and Part B, the allowable ICOSxPD-1 antibody dosing window for C1D15 is ±1 day; from Cycle 2 and higher, the window is ±3 days. If a subject’s dose of an ICOSxPD-1 antibody is held for > 7 days in any cycle in Part A or Part B, it should be considered missed. [00245] An ICOSxPD-1 antibody is administered by TV infusion at a constant rate over 1 hour. Ipilimumab is administered at a dose of 1 mg/kg over a 90-minute IV infusion. On days when both ipilimumab and an ICOSxPD-1 antibody are administered, ipilimumab is given first and an ICOSxPD-1 antibody is started 60 minutes after the end of the ipilimumab infusion.

[00246] Part A: Dosing Schedule for Dose-Escalation Phase

[00247] In Part A of the study, subjects are enrolled into dose-escalation cohorts to establish an MTD/RD(s) for a dosing regimen consisting of infusions administered every 2 weeks on Days 1 and 15 of each 28-day cycle.

[00248] Ten dose levels are planned for Part A as follows: 0.002, 0.02, 0.06, 0.2, 0.6, 1.8, 5.4, 10.0, 15.0, and 20.0 mg/kg with the potential to continue to escalate beyond dose level 10, if the safety profile allows, and each higher dose level representing a < 50% increase above the immediately prior dose level.

[00249] During Part A, the first subject in each dose-escalation cohort is dosed and observed for a minimum of 24 hours before study drug is subsequently administered to the remainder of subjects enrolled in the cohort. The dose level increases initially proceed according to an accelerated titration design, as shown in Table 2.

Table 2. Dose Levels and Dose-Escalation Schema

[00250] During the initial accelerated dose-escalation phase (Cohorts 1 A and 2A), dose escalation proceeds as described in Table 3.

Table 3. Dose-Escalation Rules

[00251] Part B: Dosing Schedule for Expansion Phase

[00252] In Part B, the treatment period for each subject on ipilimumab is 2 cycles. Each cycle is 28 days long, with each ipilimumab dose occurring every 3 weeks, as shown in Table 4.

Table 4. Dosing Schedule of an ICOSxPD-1 Antibody and Ipilimumab in Combination Group in Expansion Phase of the Study

[00253] Three induction doses of ipilimumab are planned in 2 cycles, but up to 4 total induction doses of ipilimumab are allowed should the subject continue treatment beyond 2 cycles. If a subject’s dose of an ICOSxPD-1 antibody or ipilimumab is not given within ± 3 days of the scheduled C2D1 or C2D8 visits, it is considered missed. For these specific visits, the ±3- day window supersedes the > 7-day window for any cycle provided above for missed dose. The dosing window for ipilimumab at C1D15 is ±1 day and for C3D1, it is ±3 days.

[00254] Continuation of Therapy

[00255] Subjects may receive XmAb®23104 beyond 2 cycles. For subjects in the ipilimumab group in Expansion (Part B) who continue to receive XmAb®23104 beyond 2 cycles, the fourth and final induction dose of ipilimumab will be given. If XmAb®23104 is discontinued, ipilimumab must also be discontinued such that any remaining doses of ipilimumab, as applicable, would not be administered. For all subjects who continue beyond2 cycles, tumor assessments will be repeated after every 2 cycles of therapy using the same modality.

[00256] Subj ects who experience confirmed disease progression while on treatment with XmAb®23104 but wish to continue receiving the study drug will be re-consented with a separate consent form to ensure they are aware of all treatment options and therapies that they may be foregoing.

[00257] Intra-subject dose escalation is permitted in the study. If a subject tolerates his/her dose level of XmAb®23104 for 6 months (to allow assessment for irAEs that may occur outside the DLT period), no more than 1 DLT has occurred in the cohort at the next higher dose level when all subjects in that cohort have completed the DLT period, the DERC has made the decision that the next higherdose level is tolerable, and the subject meets the specified criteria, he/she may be treated at the higher dose level.

[002581 Subjects will return for follow-up 14, 28, and 90 days after XmAb®23104 discontinuation, unless disease progression requiring initiation of other anti-cancer therapy has occurred before that time.

5.6 Study Drug and Storage

[00259] ICOSxPD-1 antibody

[00260] The ICOSxPD-1 antibody is a humanized bispecific monoclonal antibody (bsAb) that binds both PD1 and ICOS. An ICOSxPD-1 antibody drug product is supplied as a 100 mg vial consisting of a solution of 10 mg/mL ICOSxPD-1 antibody in 20 mM acetate, 250 mM sorbitol at pH 5.5, filled to a volume of 10.0 mb. IV Solution Stabilizer (IVSS), which is used to stabilize ICOSxPD-1 antibody infusions for subjects in the first 3 dose level cohorts, consists of 250 mM sodium citrate, pH 5.5 and 1.0% (w/v) polysorbate-80.

[00261] An ICOSxPD-1 antibody drug product and IVSS are stored under refrigeration at 2°C to 8°C. Both an ICOSxPD-1 antibody drug product and IVSS do not contain preservatives and thus opened vials must be used within 24 hours.

[00262] Ipilimumab (Yervoy®)

[00263] Ipilimumab (Yervoy®) is a human cytotoxic T-lymphocyte antigen 4 (CTLA4)- blocking antibody. It is administered at the 1 mg/kg dose as a diluted solution according to the package insert for all tumor type groups in Expansion (Part B) over 90 minutes through an IV line once every 3 weeks. It is supplied as a 50 mg/10 mL (5 mg/mL) solution in a single-dose vial. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid, mannitol, polysorbate 80 (vegetable origin), sodium chloride, tris hydrochloride, and Water for Injection, USP at a pH of 7.

[00264] Ipilimumab is stored under refrigeration at 2°C to 8°C. It cannot be frozen or shaken and must be protected from light, as per the ipilimumab prescribing information (Yervoy® (ipilimumab) [package insert], Princeton, NJ: Bristol-Myers Squibb Co.; 2020). The diluted solution is stored for no more than 4 hours under refrigeration (2°C to 8°C) or at room temperature (20°C to 25°C).

5.7 Study Drug Preparation and Handling

[00265] ICOSxPD-1 antibody (XmAb®23104) [00266] For administration, an TCOSxPD-1 antibody is diluted to the required final concentration in an infusion bag containing 0.9% Sodium Chloride Injection, USP, and the vial containing parenteral drug product is inspected visually. For Cohorts 1-3 in Part A (0.002, 0.02, and 0.06 mg/kg dose levels), IVSS is added to the infusion bag as well.

[00267] After dilution, the bag containing an ICOSxPD-1 antibody is gently inverted 2 to 3 times to mix the solution. The bag must not be shaken, as excess agitation may cause aggregate formation and foaming of IVSS.

[00268] Ipilimumab (Yervay®)

[00269] Ipilimumab injection is a clear to slightly opalescent, colorless to pale-yellow solution that requires dilution for IV infusion. Parenteral drug products are inspected visually for particulate matter and discoloration prior to administration.

[00270] Vials are allowed to stand at room temperature for approximately 5 minutes prior to preparation of infusion. The required volume of ipilimumab is then withdrawn and transferred into an IV infusion bag.

[00271] Ipilimumab is diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. The diluted solution is mixed by gentle inversion.

5.8 Treatment of Subjects: Administration of Study Treatment

XmAb® 23104

[00272] XmAb®23104 has not been given to humans outside of this study; hence, the toxicity profile associated with this agent is not well known and caution should be exercised as infusion reactions, allergic reactions, or other unexpected reactions may occur.

[00273] Prior to dilution, the vial containing parenteral drug product should be inspected visually. If particulate matter and/or discoloration are noted, drug should not be administered, and the Sponsorshould be notified.

[00274] XmAb®23104 administration should begin as soon as possible after the dosing solution is made. Ifthere is a delay in administration, the dosing solution may be stored at room temperature for no more than 4 hours, or for 24 hours at 2°-8°C prior to infusion (see Pharmacy Manual for additionaldetails). The full, calculated dose will be administered based on the subject’s actual baseline weight measurement in kilograms. A subject’s first dose is based on the Day -1 baseline weight in kilograms. A Cycle 1 Day 1 baseline weight may be used to calculate the first dose per institutional policy; in this case, the Cycle 1 Day 1 baseline weight will be entered in the Day -1 eCRF. Subsequent doses will be modified only if the subject’s weight changes by more than 10%from the baseline weight, at which point the dose will be recalculated using the subject’s current weight. At that time, a new baseline weight will be established such that a subsequent weight change by > 10% from the new baseline weight would require further recalculation of the XmAb®23104 dose.

[00275] XmAb®23104 should not be administered as an iv push or bolus.

[00276] XmAb®23104 will be administered as an open-label solution at a constant rate over a 1-hour period(-5 minutes/+ 15 minutes) by IV infusion. Due to pump accuracy variations, infusions ending within 5 minutes prior to the required 1-hour infusion period will not be considered a deviation.

[00277] Precautions for infusion reactions/anaphylaxis should be observed during XmAb®23104administration. Due to the possibility that allergic/infusion reactions may occur, emergency resuscitation equipment (a “crash cart”) should be present in the immediate area where subjects are receiving their infusions. Additional supportive measures should be available and may include, but are not limited to, the following: acetaminophen, antihistamines, corticosteroids, IV fluids, bronchodilators, epinephrine, vasopressors, diphenhydramine, and oxygen.

[00278] Vital signs will be measured and recorded as follows: preinfusion; during the infusion at 30 minutes from the start time of the infusion; at the end of the infusion (EOI); and at 30 and60 minutes after EOI, then hourly for the remainder of the required observation period of 4 hours.

[00279] All supportive measures consistent with optimal subject care will be provided throughout the studyaccording to institution standards. For subjects who tolerate 3 consecutive infusions without an infusion reaction during the observation period, the post-infusion observation period and vital signs assessment may be reduced from 4 hours to 2 hours.

Ipilimumab (Yervoy®)

[00280] In the Expansion (Part B) dosing groups incorporating ipilimumab, ipilimumab will be administered by IV infusion beginning on Day -7 before the first XmAb®23104 dose at C1D1 and every 3 weeks (in a 28-day cycle) thereafter, following the completion of all required and applicable predose procedures and assessments, for up to 4 total induction doses. On days when both ipilimumab and XmAb®23104 are administered, ipilimumab will be given first;

XmAb®23104will be started 60 minutes after the end of the ipilimumab infusion. Vital signs associated with theipilimumab infusion will be measured and recorded as follows: preinfusion and at 15 minutes (± 2min) after EOI. On ipilimumab-only administration days, the subject may be discharged as soon 15 minutes post-infusion, following the vital signs (and ECG) measurements if stable; on days when both the XmAb®23104 and ipilimumab are administered, the subject may be discharged if stable after the required XmAb®23104 observation period. [00281] Ipilimumab will be administered at a dose of 1 mg/kg over a 90-minute IV infusion. Sites should make every effort to target infusion timing to be as close to 90 minutes as possible. However, giventhe variability of infusion pumps from site to site, a window between -5 minutes and +15 minutesis permitted (i.e., infusion time is 90 minutes [-5 min/+15 min]). For additional information, refer to the ipilimumab prescribing information (Yervoy, Package Insert, 2020, supra).

[00282] The full, calculated dose of ipilimumab will be administered based on the subject’s actual baselineweight measurement in kilograms. A subject’s first dose is based on the Day -7 baseline weight in kilograms. The subject’s weight that is used to calculate the XmAb®23104 dose at C1D15 and C3D1 will be used for both ipilimumab and XmAb®23104 when they are dosed on the same day. On the C2D8 visit when ipilimumab is administered alone, if a subject’s weight has changed by more than 10% from the previous baseline weight (at C1D15), the dose will be recalculated usingthe subject’s current weight.

[00283] Ipilimumab solutions must not be administered as an iv push or bolus injection.

5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Assessments

[00284] Serum Sampling for Pharmacokinetic Analyses, Pembrolizumab Level, Nivolumab

Level, Anti-Drug Antibodies, and Cytokines/Inflammatory Factors

[00285] Venous blood samples for serum analyses of ADA and the cytokine panel are obtained according to the schedule listed in Table 5A and Table 5B. ADA samples may also be analyzed for soluble factors such as soluble PD-1 and soluble ICOS that can interfere with the assay. Venous blood samples for analyses of PK are obtained according to the times specified in Table 6 Table 5A. Schedule of Assessments for Parts A and B

Table 5B: Schedule of Assessments for Parts A and B (Continued)

ACTH = adrenocorticotropic hormone; ADA = anti -drug antibody; [i-hCG = beta unit of human chorionic gonadotrophin; CBC = complete blood counts; d = days; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffinized embedded; FSH = follicle-stimulating hormone; fT4 = free thyroxine; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; Hgb A1C = hemoglobin A1C; HIV = human immunodeficiency virus; min = minute; m = month; PBMC = peripheral blood mononuclear cells; PE = physical examination; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; T3 = triiodothyronine; TSH = thyroid-stimulating hormone ^a Collect FFPE tumor sample or unstained slides (refer to lab manual) Fresh tumor biopsies should be obtained for Part A subjects and are mandatory for Part B subjects. A second fresh tumor biopsy (mandatory for Part B subjects) is obtained on Day 21-28 of Cycle 1 and should come from the same site as the screening biopsy unless there are patient safety concerns or issue with tissue availability. Biopsies of tumors should occur on non-target lesions, if feasible. For Part A, subjects need to specifically consent to having this optional biopsy at both time points However, if archival tumor sample is not available or is insufficient, the screening tumor biopsy to provide a fresh tumor sample in lieu of the archival tissue becomes mandatory for study participation. For Part B, it is mandatory; if a subject declines, the subject is not be able to participate in the study. Leftover tissue from the fresh tumor biopsy sample may be saved for biobanking. Biobanking is optional and requires specific subject consent. ^b Complete medical history and PE at screening. For all the other time points an abbreviated, symptom-directed history and PE is to be performed. ^c Supine BP and pulse rate, body temperature, respiratory rate. On days of an ICOSxPD-1 antibody infusions, vital signs should be taken preinfusion and 30 minutes after start of infusion (±10 min), at the end of infusion (EOI) (±5 min), and 30 and 60 minutes after EOI (±10 min), then hourly (±10 min) after EOI for the remainder of the required observation period. On days of ipilimumab infusions, vital signs associated with the ipilimumab dosing should be taken preinfusion and 15 min (±2 min) after the EOI of ipilimumab

All vital signs during infusion should be taken with subject in the same position. Subjects are observed for at least 4 hours following the end of the first 3 an ICOSxPD-1 antibody infusions. The observation period and vital signs assessments may be decreased to 2 hour's if there are no infusion reactions for 3 consecutive an ICOSxPD-1 antibody infusions. Subjects may be discharged at the end of the observation period if stable: as soon as 15 min after the ipilimumab EOI, following the ECG and vital signs measurements on ipilimumab -only days or following the required an ICOSxPD-1 antibody observation period when an ICOSxPD-1 antibody is also administered. ^d On dosing days in Part A of the study, ECGs should be performed prior to infusion, within 5-30 minutes after EOI , and if clinically indicated. On dosing days in the first 2 cycles of therapy of Part B, ECGs should be performed prior to infusion, within 5-30 minutes after EOI , and if clinically indicated for both ipilimumab and the ICOSxPD-1 antibody, as applicable;. On dosing days after the first 2 cycles of therapy in Part A and Part B, ECGs should be performed prior to ipilimumab and an ICOSxPD-1 antibody infusion, as applicable. Day -1 ECG is not needed as long as one is completed during Screening for eligibility review and at Cycle 1 Day 1 preinfusion. ^e May be performed up to 24 hours prior to infusion. The following procedures that are completed on Day -1 within 24 hours of Cycle 1 Day 1 dosing do not need to be repeated on Cycle 1 Day 1 : PE, ECOG, and local safety laboratories (eg, CBC with differential and platelets, chemistry panel, coagulation panel, and urinalysis). These safety' testing are performed by both the central laboratory and local clinical site laboratories to allow review of the results by clinical site personnel before an ICOSxPD-1 antibody infusion Local “safety” tests are per institutional practice; these local laboratory results may be used for decisions on dosing. Similarly, these Day -7 procedures (PE, ECOG, safety laboratory sampling) may be performed up to 24 hours prior to infusion if it is per institutional practice. ^f Once postmenopausal status has been established by FSH, this test need not be repeated during the clinical trial. ^g May be performed up to 4 weeks prior to screening

¹¹ Cortisol should be drawn as close to 8 AM as possible on an ICOSxPD-1 antibody dosing days and post-treatment period only.

‘ Pre-infusion (to both an ICOSxPD-1 antibody and ipilimumab on combination days) on day of dose. Flow cytometry, cytokine levels, nucleic acids, and PBMC are not required after Cycle 4 Day 1. An EOT sample should be collected for flow cytometry and cytokines. j Biobanking of nucleic acids and PBMC should be obtained. If unscheduled samples are collected for routine biomarker testing, the leftover material may be biobanked. Biobanking is optional and requires specific subject consent ^k An ICOSxPD-1 antibody dosing window for Cycle 1 Day 15 is ±1 day and ±3 days for Cycle 2 and higher An ICOSxPD-1 antibody is administered as a 1-hour (- 5 min / + 15 min) IV infusion. Subjects are observed for at least 4 hours following the first 3 infusions. The observation period and vital signs assessments may be decreased to 2 hours if there are no infusion reactions for 3 consecutive infusions.

¹ See Table 6 for sampling times. Samples are not required at Cycle 13 and higher. ^m Preinfusion (to both an ICOSxPD-1 antibody and ipilimumab on combination days) on day of dose. For Cycles 3 through 12 (samples are not required at Cycle 13 and higher), ADA sampling is performed on Day 15 only. Subjects with a positive ADA at termination are followed every 28 days (± 3 days), if feasible, until ADA reverts to baseline or until the next intervening treatment. ⁿ This sampling needs to be performed predose for the first dose of an ICOSxPD-1 antibody on Day 1 of Cycles 1 and 2 and subsequent cycles within 2 days, if applicable, only for those subjects who have previously received pembrolizumab or nivolumab within 24 weeks. Samples are not required at Cycle 13 and higher.

⁰ Tumor assessment (including radiologic imaging) per RECIST (RECIST 1.1, iRECIST, and imRECIST) at baseline, at the end of Cycle 2, and at the end of every second cycle of treatment thereafter. All studies for the baseline assessment should be performed within 14 days prior to the first dose of an ICOSxPD-1 antibody in Escalation (Part A) or 21 days prior if assigned to monotherapy in Expansion (Part B): 14 days prior to first dose of ipilimumab if assigned to combination therapy in Expansion (Part B). EOT assessment should be performed only if such an assessment has not been performed in the past 60 days. A baseline assessment performed within 14 days prior to the first dose of study drug, but prior to the signing of the informed consent, may be utilized. On-treatment assessments should be performed on a calendar schedule and not be affected by delays or adjustments in treatment. ^p Dosing days for Cycle 2 and higher have a window of ±3 days; the 14-day, 28-day, and 90-day post-EOT visits have a window of ± 3 days; the 6 and 12 months post-EOT follow-up is ±7 days. ^q PK samples on Day 15 at the 3-hour and 10-hour time points are collected at Cycle 2 only; PK samples on Days 16, 17, and 22 are collected at Cycle 2 only. ^r The screening window for Escalation (Part A) is from Day -28 to -2; for Expansion (Part B), it is from Day -35 to -9. ^s In Expansion (Part B), applicable for subjects randomized to the ipilimumab combination arm only.

¹ On days when both ipilimumab and an ICOSxPD-1 antibody are administered, ipilimumab is given first; an ICOSxPD-1 antibody infusion starts 60 minutes after the end of the ipilimumab infusion. Ipilimumab is administered as a 90 min (-5 min / +15 min) IV infusion. If the fCOSxPD-1 is discontinued, ipilimumab must also be discontinued The dosing window for ipilimumab at Cycle 1 Day 15 is ±1 day; at Cycle 2 Day 8 and Cycle 3 Day 1, it is ±3 days.

“ The randomization applies to Part B only.

Table 6. Sampling for Pharmacokinetics for Parts A and B

EOI = end of infusion (from Cycle 1 Day 1 dose); EOT = end of treatment; h = hour(s); min = minutes; PK = pharmacokinetics. ^a PK samples under “Cycle 2 through Cycle 12” on Day 15 at the 3h and lOh time points, and 24h, 48h, 168h time points corresponding to Days 16, 17, and 22 are collected at Cycle 2 only. On visits where An ICOSxPD-1 antibody and ipilimumab are dosed on the same day, pre-dose PK to be done before ipilimumab.

[00286] Pharmacokinetics

[00287] Samples for PK analysis are collected at the times specified in Tables 5A, 5B, and 6.

The exact time and date of the blood draw must be accurately recorded using an unambiguous format such as DD MMM YYYY and HH:MM on a 24-hour clock.

[00288] Serum samples for measurement of pembrolizumab or nivolumab levels are collected at the times specified in Table 4 for all subjects who have previously been treated with pembrolizumab or nivolumab, respectively.

[00289] Pharmacodynamics in Peripheral Blood and Tumor

[00290] Baseline and serial assessment of inflammatory indices are examined in peripheral venous blood. Inflammatory indices measured longitudinally include serological assessment of soluble factors, ribonucleic acid (RNA) assays and flow cytometric analysis for a) receptor occupancy, b) immune cell numbers (T/B/NK assay) and c) T-cell subset activation/proliferation. [002911 Archival, pre- and post- An ICOSxPD-1 antibody fresh tumor biopsies (fresh biopsies are optional for Part A subjects who have adequate archival tumor tissue and mandatory for Part B subjects) are to be examined by the following: immunohistological characterization of the tumor immune infdtrate and expression of immunomodulators, including ICOS and PD-1/PD-L1 and other immunoregulatory markers of activation and proliferation; by transcriptional RNA inflammatory signatures, and by next generation sequencing analysis of mutational burden.

[00292] The sampling schedule for these assessments is shown in Tables 5A, 5B, and 6. The initial biomarkers being explored in this study are shown in Table 7.

Table 7. Biomarkers

[00293] Biobanking Samples

[00294] Fresh tumor biopsies and peripheral blood are collected as biomarker samples. On treatment biomarker samples are compared with baseline biomarker samples for inflammatory changes in the TME that might inform (1) use of baseline material to predict response to An ICOSxPD-1 antibody and (2) use of potential combination therapies to overcome mechanisms of resistance. DNA, RNA, and protein levels are used from the biomarker samples to assess the interaction of the tumor and its microenvironment. An ICOSxPD-1 antibody aims to enlist T cells to kill tumor cells, so the studies focus on both the oncogenic characteristics of the tumor cells and the expression of immunomodulatory genes and proteins on both the tumor cell target and the immune cells that contribute to killing, which include T cells and other cells of the antitumor inflammatory response.

5.10 Assessment of Efficacy

[00295] The objective of these analyses is to explore in a preliminary manner the effects of An ICOSxPD-1 antibody when administered repeatedly across a range of dose levels, as monotherapy or in combination with ipilimumab, and at the final MTD or RD.

[00296] The assessment of anti -tumor effects of an ICOSxPD-1 antibody, as monotherapy or in combination with ipilimumab, is based on response criteria defined in RECIST 1.1 and in imRECIST and iRECIST (refer to Table 8).

[00297] The number and percentage of subjects achieving a best response of complete response (CR; confirmed and unconfirmed), partial response (PR; confirmed and unconfirmed), stable disease (SD), PD, and not evaluable is presented.

[00298] Preliminary anti -turn or activity using RECIST 1.1, imRECIST, and iRECIST assessment as well as aggregate data for all subjects for ORR, best overall response rates, PFS, and DOR.

[00299] The ORR is defined as the proportion of subjects who achieved an overall response of PR or better, confirmed or not confirmed. The number and percent of subjects who achieved ORR is summarized. Two-sided exact 95% Cis for the ORR is determined using the binomial distribution. The duration of objective response is calculated from the time of initial response (PR or better) to the first documentation of relapse (recurrence after CR) or progression (after PR).

[00300] The efficacy population is used for summary of ORRs, best overall responses, PFS, and DOR. Additional sensitivity analyses using the evaluable population may be performed. [00301] Depending on the completeness of the available follow-up data, an analysis of PFS, measured relative to Day 1, is performed based on the Kaplan-Meier method. Median time and its 95% CI, as well as the 25th and 75th quartiles with their 95% CI, is summarized. Progression is determined using the criteria described in RECIST 1.1, imRECIST, and iRECIST. The date of progression is defined as the date of progression or death. The date of censoring for subjects who end the study without documented progression correspond to the date the last tumor assessment was performed. Subjects who terminated from study without postbaseline tumor assessment are censored at Day 1.

[00302] The potential anti -tumor effects of an ICOSxPD-1 antibody may also be evaluated in other subgroups of subjects.

Table 8. Comparison Between RECIST 1.1, imRECIST, and iRECIST

CR = complete response; CRF = case report form; iCPD = immune-confirmed progressive disease; imRECIST = immune-modified RECIST; iRECIST = modified RECIST for immunebased therapeutics; iUPD = immune unconfirmed progressive disease; PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors; SLD = sum of longest diameter. ^a imRECIST — follow RECIST 1.1 conventions unless otherwise stated.

5.11 Dose Modification

[00303] The following table shows treatment guidelines for TCOSxPD-1 antibody treatment- related infusion-related reactions:

Table 9. ICOSxPD-1 Antibody Infusion Reaction Dose Modification and Treatment

Guidelines

IV/iv = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events; NSAID = nonsteroidal anti-inflammatory drugs; po = oral.

Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related

Adverse Events

CTCAE = Common Terminology Criteria for Adverse Events; DILI = drug-induced liver injury; irAE = immune-related adverse event; IV = intravenous; T1DM = type 1 diabetes mellitus; ULN = upper limit of normal. ¹ Withhold or permanently discontinue TCOSxPD-1 antibody is at the discretion of the investigator or treating physician.

For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of ICOSxPD- 1 antibody is required, the drugs may be resumed when AE resolves to Grade < 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).

5.12 Results

[00304] Subjects treated with an ICOSxPD-1 antibody of the disclosure are expected to have improved therapeutic outcomes compared to subjects treated with another TCOSxPD-1 antibody and/or subjects treated with another suitable therapy for a solid tumor.

EXAMPLE 2 - A Phase 1 multiple-ascending dose study to evaluate the safety and tolerability of an ICOSxPD-1 antibody in patients with selected advanced solid tumors

[00305] A phase 1 study is conducted to assess the safety and tolerability profde of an ICOSxPD-1 antibody of the disclosure in patients with advanced solid tumors and to determine the maximum tolerated dose (MTD). The expansion part of the study enrolls patients with colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), non-squamous, non-small cell lung cancer (NSCLC), sarcoma, melanoma, and clear-cell renal cell carcinoma (RCC). Results showed that an ICOSxPD-1 antibody of the disclosure (e.g, XmAb®23104) was well tolerated and exhibited a distinct safety profde compared to other clinical ICOS programs. Secondary objectives were designed to assess pharmacokinetics (PK), immunogenicity, and preliminary anti-tumor activity.

Methods

[00306] An ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) was administered biweekly and RECIST 1.1 assessment was performed every 8 weeks (FIG. 3). A 3+3 monotherapy dose escalation with 9 dose levels from 0.002 to 15 mg/kg was performed. Patients with measurable disease who progressed on prior standard therapy were eligible. However, a minimum of 6-week washout from prior pembrolizumab treatment was required.

Key Inclusion Criteria

[00307] Histological or cytological confirmation of an advanced solid tumor; measurable disease by RECIST 1.1; disease progression on standard of care therapy; and ECOG 0 or 1.

Key Exclusion Criteria: [00308] Prior TCOS therapy; grade 4 related adverse event from prior immunotherapy; active CNS involvement; and active known or suspected autoimmune disease.

Overview

[00309] At the data cut off on April 15, 2022, 62 patients were treated in nine dose-escalation cohorts escalating from 0.002 mg/kg to 15 mg/kg of an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) administered every other week in four-week cycles (Table 11). Subjects were a median age of 63 years and had a median of three prior systemic therapies. The demographics of the patients, baseline characteristics, and patient disposition are shown in Table 12, Table 13, and Table 14, respectively. 62.9% of patients had received at least one prior checkpoint therapy, and 91.9% of the patients had Stage IV disease. Patients had the following primary tumor types: CRC (n=14), pancreatic adenocarcinoma (n=8), soft tissue sarcoma (n=8), melanoma (n=6), HNSCC (n=5), RCC (n=4), endometrial cancer (n=2), NSCLC (n=2), and other solid tumor types (n=8). Of the patients with CRC, eight were microsatellite stable (MSS) and three were microsatellite instable (MSI). Most patients had tumors generally not considered to be sensitive to checkpoint inhibition.

Table 11. Exposure to Treatment by Starting Dose level

Table 12. Demographics of the Patients

Table 13. Baseline Characteristics

(STS) soft tissue sarcoma; (NSCLC) non-squamous non-small cell lung carcinoma; (HNSCC) head and neck squamous cell carcinoma; (CRC) colorectal cancer; (PDA) pancreatic cancer;

(RCC) renal cell carcinoma; (EC) endometrial cancer.

Table 14. Patient Disposition

XmAb®23104. ^b Anti-tumor activity evaluable population is defined as all subjects who have completed Cycle 2, received all 4 infusions of XmAb®23104 and have at least 1 post baseline RECIST 1.1 assessment. ^c The subject’s last dose is the same as or beyond the last scheduled dose of the cycle

Safety and Tolerability

[00310] Safety was evaluated in all 62 patients (refer to Table 15, Table 16, Table 17, Table 18, Table 19, and FIG. 4). ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) was well tolerated through the highest tested dose cohort. It was observed that treatment-related adverse events (TRAE) were mostly mild. Thirty-seven subjects (59.7%) experienced a treatment-related adverse event (TRAE) and/or a treatment emergent adverse event (TEAE) (Table 15 and Table 16, respectively). The most common TRAEs (>5 patients) were decreased appetite (9.7%), diarrhea (9.7%), fatigue (9.7%) and maculopapular rash (8.1%). Six patients (9.7%) had a Grade 3 or higher TRAE (Table 17). Two patients (3.2%) experienced serious TRAEs, including a Grade 3 hyperbilirubinemia and a Grade 4 asymptomatic lipase increase; both events resolved with prednisone. Grade 3 and higher TEAEs are shown in Table 18. There were no significant differences in Grade >3 AEs for subjects with or without ADA responses. Thirteen immunotherapy -related adverse events (irAEs) occurred in 8 patients; no individual irAE occurred in more than 1 patient (Table 19). Most irAEs were mild (Grades 1 and 2) with 1 Grade 3 pruritus and 1 asymptomatic Grade 4 lipase elevation. Immune-related adverse events (irAEs) showed no relationship to dose level. Four patients (6.5%) discontinued from the study due to an adverse event. Nineteen subjects (30.6%) experienced serious adverse events (SAEs). SAEs reported for more than one subject were acute kidney injury and small intestinal obstruction (n=2 each). No dose-limiting toxicities were observed, and the MTD was not reached. The recommended dose for continued study, based on feasibility of administration at higher dose levels and a review of safety data, was determined to be 10 mg/kg. However, other doses are contemplated for use in the methods provided elsewhere herein. Table 15. Treatment Related Adverse Events in >1 Patient

Table 17. Treatment Related Adverse Events Grade >3 in Safety Population

Table 18. Grade 3 and Higher TEAEs Occurring in >1 Patient

Table 19. Immunotherapy Related Adverse Events

Clinical Activity Highlights

[00311] The efficacy analysis included 51 evaluable patients who received any amount of an ICOSxPD-1 antibody (e.g., XmAb®23104) and had at least one post-baseline assessment by RECIST 1.1. At data cut-off, partial responses were observed in 3 patients (sarcoma, prior PD-1 head and neck squamous cell carcinoma [HNSCC], and renal cell carcinoma [RCC]) and stable disease > 12 months was observed in 2 subjects with colorectal cancer (CRC; 2 MST-H). A dose of 10 mg/kg was selected after consideration of PK, safety, and clinical activity data and continues to be evaluated in the expansion part of the study. Two confirmed partial responses (PR), one unconfirmed PR, and stable disease was observed as below:

• A patient with undifferentiated pleomorphic sarcoma, who was immunotherapy naive, presented with two target lesions in the lung and a subpleural lingular nodule (FIG. 7A). The patient had previous radiation and surgery, but no prior disease specific therapy. The patient was enrolled into the 0.2 mg/kg cohort and dose escalated to 0.6 mg/kg (Cycle 7, Day 1). The nodule completely resolved, and a single non-target lesion remained in the lung. The patient had partial response at Cycle 2, Day 26 and is in Cycle 33 (about 28 months).

• A patient with clear cell RCC, who had previously received treatment with pembrolizumab/axitinib, presented with two target lesions in the ribs, one target lesion in a lymph node, and a non-target lesion in bone (FIG. 7B). The patient was treated at the 10 mg/kg dose. A partial response was observed at the end of Cycle 2, and the patient is in Cycle 12.

• A patient with HNSCC, who had received treatment with pembrolizumab, was enrolled into the 1.8 mg/kg dose cohort (FIG. 7C). Prior therapies also included neo-adjuvant nivolumab, cisplatin, nivolumab, GAL-3 inhibitor, and recent (2 months) pembrolizumab. The patient experienced disease progression on all prior therapies. Two target lesions in the lung were identified, and the patient experienced a partial response at the end of Cycle 2 (Cycle 2, Day 26). The patient progressed after 4 cycles of treatment.

• Two patients with CRC experienced durable stable disease for over 20 months, both ongoing.

A patient with microsatellite instability high (MSI-H)-CRC was treated at an initial dose of 1.8 mg/kg and dose escalated to 10 mg/kg (e.g, 1.8 mg/kg, 5.4 mg/kg, and 10 mg/kg). Laboratory results indicated a decrease in the tumor marker CEA over time. This subject was heavily pretreated with 5 lines of prior therapies including a complete response on FOLFOX and stable disease on pembrolizumab. Five target lesions were identified and stable disease has been observed for over 2 years. This subject escalated to 5.4 mg/kg at C7D1 then to 10 mg/kg at Cl 3D 1. The subject experienced a Grade 3 small bowel obstruction and other mild adverse events, none of which were reported as related to study drug.

- A second patient, with (MSI-H) CRC, was treated at the 10 mg/kg dose and is in Cycle 22 with no related AEs > grade 1. The second patient progressed on all prior therapies including FOLFOX + bevacizumab, nivolumab/ipilimumab, and maintenance nivolumab. The second patient has been stable for 22 months after treatment with an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104). Thi subject experienced mild adverse events (Grade 1) none of which are reported as related to study drug.

Pharmacokinetics/Pharmacokinetics Assessments

[00312] The PK analysis indicated a linear and dose-proportional profile (FIGS. 5A-5C). The mean serum half-life of an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) was estimated to be 10.6 days. A high incidence of anti-drug antibody (ADA) responses were observed, but no impact on PK was observed at doses higher than 0.06 mg/kg. Biomarker analyses indicated complete receptor saturation on peripheral T cells beginning at the 0.6 mg/kg dose level (FIG. 6).

Summary of results

[00313] XmAb®23104 is a bispecific antibody targeting T cells that simultaneously express PD-1, an immune checkpoint, and ICOS, a costimulatory molecule expressed after T cell activation. DUET-3 is a Phase 1, first-in-human, dose-escalation and expansion study in subjects with advanced solid tumors, designed to assess safety, tolerability and to identify the maximum tolerated dose (MTD) of XmAb®23104. Secondary objectives are to assess pharmacokinetics (PK), immunogenicity, and preliminary anti-tumor activity. Preliminary data is provided from a 3+3 monotherapy dose escalation with 9 dose levels from 0.002 to 15 mg/kg, which has been completed.

[00314] Subjects with measurable disease who progressed on prior standard therapy were eligible A minimum 6-week washout from prior pembrolizumab was required XmAb®23104 was administered biweekly and RECIST 1.1 assessment was performed every 8 weeks. [00315] Sixty -two subjects were treated in escalation at doses up to 15 mg/kg; no doselimiting toxicides were observed and an MTD was not reached. These subjects had advanced disease, 92% were Stage IV at screening, the median number of prior therapies was 3, and 37% had previous checkpoint therapy. Thirty-seven subjects (59.7%) experienced a treatment-related adverse event (TRAE); the most common were diarrhea (9.7%), decreased appetite (9.7%), and fatigue (9.7%). The majority of TRAEs were Grades 1 or 2, with 6 subjects (9.7%) having a Grade 3 or higher TRAE. Thirteen immunotherapy -related adverse events (irAEs) occurred in 8 subjects; no individual irAE occurred in more than 1 subject. Most irAEs were mild (Grades 1 and 2) with 1 Grade 3 pruritus and 1 asymptomatic Grade 4 lipase elevation.

[00316] Partial responses were observed in 3 subjects (sarcoma; prior PD-1 head and neck squamous cell carcinoma [HNSCC] and renal cell carcinoma [RCC]), and stable disease > 12 months was observed in 2 subjects with colorectal cancer (CRC; both MSI-H). A dose of 10 mg/kg was selected after consideration of PK, safety, and clinical activity data in consultation with the investigators and continues to be evaluated in the expansion part of the study.

Conclusions

[00317] In preclinical studies, it was observed that dual blockade of PD-1 and ICOS with an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) significantly enhanced T cell proliferation and activation, and anti -tumor activity in vivo. The ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) provides for dual checkpoint inhibition and such co-stimulation reduces the need for multiple antibodies while allowing for more selective targeting of T cells with high target expression, which can potentially improve the therapeutic index of combination immunotherapies.

[00318] The dose escalation part of this study indicated that an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) was well tolerated at doses up to 15 mg/kg (doses ranging from 0.002 to 15 mg/kg) and showed clinical activity in patients with advanced solid tumors.

[00319] In brief, results showed that no dose limiting toxicides (DLTs) were observed, that MTD was not reached, that a maximum feasible dose of 10 mg/kg was selected as the recommended dose based on safety profile and clinical activity, and that there was no significant differences in Grade >3 AEs for patients with or without ADA. Immune-related adverse event (irAE) were reported for a limited percentage of patients (predominantly Grades 1 and 2) and showed no relationship to dose. Results also showed that partial responses to therapy were observed at doses as low as 0.2 mg/kg and in different tumor types. PK data showed that PK was linear and exposure was not affected by recent prior pembrolizumab treatment (presence of ADA did not affect exposure at doses higher than 0.06 mg/kg). Further, target engagement was observed at 0.2 mg/kg (65%) and was saturated (100%) at 0.6 mg/kg and higher doses. Overall, results showed that an ICOSxPD-1 antibody of the disclosure (e.g., XmAb®23104) is effective in treating advanced solid tumor types including HNSCC, NSCLC, CRC, sarcoma, melanoma, and ccRCC.

[00320] XmAb®23104 is currently being studied alone or in combination with ipilimumab in an expansion portion of the study for patients with colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), non-squamous, non-small cell lung cancer (NSCLC), sarcoma, melanoma and clear-cell renal cell carcinoma (RCC), and is randomizing patients 1 : 1 to receive 10 mg/kg intravenous XmAblO4 every two weeks as monotherapy or in combination with ipilimumab to increase the frequency of ICOS-expressing T cells in multiple solid tumor types.

[00321] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description.

[00322] Although the invention is described in detail with reference to specific embodiments thereof, it will be understood that variations which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

What is claimed is:

1. A method of treating a solid tumor in a subject in need thereof, wherein the method comprises: administering to the subject a multispecific antibody comprising a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1 (ICOSxPD-1 antibody), wherein: a) the first antigen binding domain that binds to ICOS comprises: i. a heavy chain variable (VH) domain comprising a VH complementaritydetermining region (CDR) 1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and ii. a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and VL CDR3 having an amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and b) the second antigen binding domain that binds to PD-1 comprises: i. a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NOV, respectively; and ii. a VL domain comprising a VL CDR1 , a VL CDR2, and VL CDR3 having an amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; and wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg to about 30 mg/kg, thereby treating the solid tumor.

2. The method of claim 1, wherein the VH of the first antigen binding domain comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 13.

3. The method of claim 1 or 2, wherein the VL of the first antigen binding domain comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 14. A method of treating a solid tumor in a subject in need thereof, wherein the method comprises: administering to the subject a multispecific antibody comprising a first antigen binding domain that binds to ICOS and a second antigen binding domain that binds to PD-1 (ICOSxPD-1 antibody), wherein the ICOSxPD-1 antibody comprises: a) a first monomer comprising, from N- to C-terminus, a scFv-linker-CH2-CH3 comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 15; b) a second monomer comprising, from N- to C-terminus, a VH-CHl-hinge-CH2- CH3 comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 16; and c) a third monomer comprising, from N- to C-terminus, a VL-CL comprising an amino acid sequence comprising about or at least about 90% sequence identity to SEQ ID NO: 17, and wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg to about 30 mg/kg of the ICOSxPD-1 antibody, thereby treating the solid tumor. The method of claims 4, wherein the scFv comprises a sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. The method of claim 4 or 5, wherein the scFv of the first monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8; a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 9; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 10; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 11; and/or a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 12. The method of any one of claims 4-6, wherein the VH of the second monomer comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1; a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2; and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3. The method of any one of claims 4-7, wherein the VL of the third monomer comprises: a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4; a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6. The method of any one of claims 1-8, wherein the solid tumor is refractory, relapsed, or refractory and relapsed solid tumor. The method of any one of claims 1-8, wherein the solid tumor is a newly diagnosed solid tumor. The method of any one of claims 1-10, wherein the solid tumor is selected from the group consisting of undifferentiated pleomorphic sarcoma (UPS), non-squamous non-small cell lung carcinoma (NSCLC), soft-tissue sarcoma, myxofibrosarcoma, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), renal cell carcinoma (RCC) with clear cell histology (ccRCC), melanoma, cervical carcinoma, pancreatic carcinoma, estrogen receptor, progesterone receptor, Her2 negative breast cancer, hepatocellular carcinoma, urothelial carcinoma, nasopharyngeal carcinoma, endometrial carcinoma, small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, and sarcoma. The method of any one of claims 1-11, wherein the solid tumor comprises tumorinfiltrating lymphocytes (TILs) having an elevated ICOS expression level compared to a reference. The method of claim 12, wherein the reference is the ICOS expression level obtained from a biological sample comprising lymphocytes obtained from the subject at an earlier time point. The method of claim 12, wherein the reference is the TCOS expression level in a biological sample comprising lymphocytes obtained from another subject or a population of subjects diagnosed with the same solid tumor as the subject. The method of claim 13 or 14, wherein the biological sample is a tumor sample. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.002 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.02 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.06 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.2 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 0.6 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 1.8 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 5.4 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 10 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 15 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 20 mg/kg. The method of any one of claims 1-15, wherein the TCOSxPD-1 antibody is administered to the subject in an amount of about 25 mg/kg. The method of any one of claims 1-15, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of about 30 mg/kg. The method of any one of claims 1-27, wherein the method comprises cyclic administration of the ICOSxPD-1 antibody. The method of claim 28, wherein each cycle of the cyclic administration is 28 days. The method of claim 28, wherein the cyclic administration comprises about or at least about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles, or more than twelve cycles. The method of claim 30, wherein the cyclic administration comprises about or at least about 2 cycles of 28 days each. The method of any one of claims 29-31, wherein the ICOSxPD-1 antibody is administered to the subject twice in one cycle. The method of any one of claims 29-32, wherein the ICOSxPD-1 antibody is administered to the subject on Day 1 and 15 of each cycle. The method of any one of claims 1-32, wherein the ICOSxPD-1 antibody is administered to the subject once every 2 weeks. The method of any one of claims 1-34, wherein the ICOSxPD-1 antibody is administered to the subject for at least 8 weeks. The method of any one of claims 1-35, wherein the administering is via intravenous administration. The method of any one of claims 1-36, wherein the administering is for about 55 to 75 minutes. The method of any one of claims 1-36, wherein the administering is for about or at least about 1 hour. The method of any one of claims 1-38, wherein the ICOSxPD-1 antibody is administered to the subject as a monotherapy. The method of any one of claims 1-39, wherein the method further comprises administering an antibody that binds CTLA-4 (CTLA-4 antibody) to the subject. The method of claim 40, wherein the CTLA-4 antibody is ipilimumab. The method of claim 40 or 41, wherein the CTLA-4 antibody is administered to the subject in an amount of about 1 mg/kg. The method of any one of claims 40-42, wherein the CTLA-4 antibody is administered to the subject a total of 3 times in 2 cycles of the cyclic administration. The method of any one of claims 40-42, wherein the CTLA-4 antibody is administered to the subject once every 3 weeks. The method of any one of claims 40-44, wherein the CTLA-4 antibody is administered for at least 8 weeks. The method of any one of claims 40-42, wherein the CTLA-4 antibody is administered to the subject at most about 3 times in 8 weeks. The method of any one of claims 40-42, wherein the CTLA-4 antibody is administered to the subject at most about 4 times in 9 weeks. The method of any one of claims 40-47, wherein the CTLA-4 antibody is administered to the subject at most 4 times. The method of any one of claims 40-48, wherein a first dose of the CTLA-4 antibody is administered to the subject before the start of the first cycle of the cyclic administration. The method of any one of claims 40-49, wherein the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle of the cyclic administration. The method of any one of claims 40-50, wherein the CTLA-4 antibody is administered to the subject on Day 15 of the first cycle of the cyclic administration. The method of any one of claims 40-51, wherein the CTLA-4 antibody is administered to the subject on Day 8 of the second cycle of the cyclic administration. The method of any one of claims 40-52, wherein the CTLA-4 antibody is administered to the subject on Day 1 of the third cycle of the cyclic administration. The method of any one of claims 40-53, wherein the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. The method of any one of claims 40-54, wherein the CTLA-4 antibody is administered to the subject intravenously. The method of any one of claims 40-55, wherein the CTLA-4 antibody is administered to the subject for about 85 minutes to about 105 minutes. The method of any one of claims 40-56, wherein the CTLA-4 antibody is administered to the subject on the same day as the ICOSxPD-1 antibody. The method of claim 57, wherein the CTLA-4 antibody is administered to the subject about or at least about 60 minutes before the ICOSxPD-1 antibody. The method of any one of claims 40-58, wherein the first dose of the CTLA-4 antibody is administered to the subject 7 days prior to the first dose of the ICOSxPD-1 antibody. The method of any one of claims 40-59, wherein the ICOSxPD-1 antibody is administered to the subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration; and wherein the CTLA-4 antibody is administered to the subject 7 days prior to the start of the first cycle of the cyclic administration, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. The method of any one of claims 40-59, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of 10 mg/kg on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration; and wherein the CTLA-4 antibody is administered to the subject in an amount of 1 mg/kg, 7 days prior to the start of the first cycle of the cyclic administration, on Day 15 of the first cycle, on Day 8 of the second cycle, and on Day 1 of the third cycle of the cyclic administration. The method of any one of claims 40-50, wherein the CTLA-4 antibody is administered to the subject between Day 14 and Day 16 of the first cycle of the cyclic administration. The method of any one of claims 40-50, wherein the CTLA-4 antibody is administered to the subject between Day 26 of the second cycle and Day 4 of the third cycle of the cyclic administration. The method of any one of claims 1-40, wherein the method does not comprise administration of an antibody that binds CTLA-4 (CTLA-4 antibody) to the subject. The method of any one of claims 1-32, 34-59, and 62-64, wherein the ICOSxPD-1 antibody is administered to the subject between Day 14 and Day 16 of the first cycle of the cyclic administration. The method of any one of claims 1-32, 34-59, and 62-64, wherein the ICOSxPD-1 antibody is administered to the subject between Day 26 of the first cycle and Day 4 of the second cycle of the cyclic administration. The method of any one of claims 1-32, 34-59, and 62-64, wherein the TCOSxPD-1 antibody is administered to the subject between Day 12 and Day 18 of the second cycle, the third cycle, and/or any consecutive cycle of the cyclic administration. The method of any one of claims 1-32, 34-59, and 62-64, wherein the ICOSxPD-1 antibody is administered to the subject between Day 26 of the second cycle or any subsequent cycle and Day 4 of the third cycle or any subsequent cycle of the cyclic administration. The method of claim 64, wherein the ICOSxPD-1 antibody is administered to the subject on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration. The method of claim 64, wherein the ICOSxPD-1 antibody is administered to the subject in an amount of 10 mg/kg on Day 1 of the first cycle, on Day 15 of the first cycle, on Day 1 of the second cycle, on Day 15 of the second cycle, on Day 1 of the third cycle, on Day 15 of the third cycle, and on Days 1 and 15 of each subsequent cycle thereafter of the cyclic administration. The method of any one of claims 1-70, wherein the method further comprises administering an additional agent to the subject. The method of claim 71, wherein the additional agent comprises epinephrine, IV fluids, antihistamines, a nonsteroidal anti-inflammatory drug, acetaminophen, a narcotic, oxygen, pressors, and/or a corticosteroid to the subject. The method of any one of claims 1-72, wherein the subject is a human subject. The method of claim 73, wherein the human subject is 18 years of age or older. The method of any one of claims 1-74, wherein the subject is a treatment-naive subject. The method of any one of claims 1-75, wherein the subject has received previous therapy and has demonstrated disease progression on previous therapy. The method of claim 76, wherein the previous therapy comprises treatment with anti-PD- 1 monotherapy, platinum-containing combination chemotherapy, anti-cancer therapy, PD-L1 therapy, PD-L2 therapy, or any combination thereof. The method of claim 76, wherein the previous therapy comprises treatment with pembrolizumab, carboplatin, pemetrexed, cisplatin, atezolizumab, paclitaxel, bevacizumab, cemiplimab-rwlc, nivolumab, cisplatin-based chemotherapy, carboplatin- based chemotherapy, afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, ceritinib, crizotinib, dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, binimetinib, or any combination thereof. The method of claim 78, wherein the previous therapy is pembrolizumab. The method of any one of claims 1-79, wherein the subject is not treated with an anti-PD- 1 antibody within 6 weeks before the method. The method of any one of claims 1-73, wherein the method results in one or more improved efficacy endpoint in the subject as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST), and/or modified RECIST 1.1 for immune-based therapeutics (iRECIST), as compared to a reference. The method of claim 81, wherein the one or more improved efficacy endpoint comprises higher percentage of objective response rate, best overall response, higher percentage of disease control rate, higher percentage of partial response, complete response, longer duration of response, longer progression-free survival, and/or longer overall survival, as compared to a reference. The method of any one of claims 1-82, wherein the size of the tumor in the subject is reduced after the ICOSxPD-1 antibody is administered to the subject as compared to a reference. The method of claim 83, wherein the reference is the size of the tumor prior to the administration of the ICOSxPD-1 antibody to the subject. The method of claim 83, wherein the reference is the size of the tumor in another subject or in a population of subjects, wherein the another subject or the population of subjects have the same type and stage of the solid tumor as the subject. The method of any one of claims 83-85, wherein the size of the tumor is reduced by about or at least about 10%, about or at least about 20%, about or at least about 30%, about or at least about 40%, about or at least about 50%, about or at least about 60%, about or at least about 70%, about or at least about 80%, about or at least about 90%, or about 100%. The method of any one of claims 82-86, wherein the one or more improved efficacy endpoint is complete response. The method of any one of claims 1-87, wherein the number of cancer cells in a biological sample obtained from the subject after the ICOSxPD-1 antibody is administered to the subject is lower as compared to a reference. The method of claim 88, wherein the biological sample is plasma. The method of claim 88, wherein the biological sample is blood. The method of claim 88, wherein the biological sample is a biopsy from the solid tumor. The method of claim 88, wherein the biological sample is serum. The method of any one of claims 88-92, wherein the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point. The method of any one of claims 88-92, wherein the reference is a predetermined value. The method of any one of claims 88-92, wherein the reference is the number of cancer cells in a biological sample obtained from a population of subjects with the same type and stage as the solid tumor. The method of any one of claims 1-95, wherein the TCOSxPD-1 antibody is XmAb®23104. The method of any one of claims 1-95, wherein the ICOSxPD-1 antibody is a biosimilar of XmAb®23104. The method of any one of claims 1-95, wherein the ICOSxPD-1 antibody is a bioequivalent of XmAb®23104.