WO2024130003A1 - Méthode de polythérapie anti-cancéreuse - Google Patents

Méthode de polythérapie anti-cancéreuse Download PDF

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WO2024130003A1
WO2024130003A1 PCT/US2023/084079 US2023084079W WO2024130003A1 WO 2024130003 A1 WO2024130003 A1 WO 2024130003A1 US 2023084079 W US2023084079 W US 2023084079W WO 2024130003 A1 WO2024130003 A1 WO 2024130003A1
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cancer
pharmaceutically acceptable
acceptable salt
her2
subject
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PCT/US2023/084079
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English (en)
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Shelley Erin ACKERMAN
Michael N. ALONSO
Cecelia Pearson
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Bolt Biotherapeutics, Inc.
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Publication of WO2024130003A1 publication Critical patent/WO2024130003A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Antibodies and immune therapeutic agents have been shown to be effective treatments that assist the immune system in cancer and disease control.
  • the simultaneous delivery of anti-tumor antibodies and therapeutic agents can be effective to treat tumors and to expand treatment options for cancer patients and other subjects.
  • the simultaneous delivery of antibodies and therapeutic agents i.e., immune agonists or immune antagonists
  • diseases, conditions, and disorders such as infections caused by viruses, bacteria, or parasites, and autoimmune diseases.
  • One way to simultaneously deliver antibodies and immune therapeutic agents is by conjugating the antibodies and therapeutic agents to form immunoconjugates.
  • Exemplary immunoconjugates and dosing regimens are described in WO 2020/190725 and WO 2021/173832, which are hereby incorporated by reference in their entireties.
  • an immunoconjugate in addition to the efficacy of an immunoconjugate being dependent on the activity and pharmacokinetic properties of the immunoconjugate (e.g., the antibodies and immune therapeutic agents) itself, the efficacy may also depend on the presence or absence of additional therapies, which can be used to supplement (e.g., amplify) the effects of the immunoconj ugate .
  • additional therapies which can be used to supplement (e.g., amplify) the effects of the immunoconj ugate .
  • combination therapies which include immunoconjugates containing antibodies and therapeutic agents that provide desirable therapeutic effects with respect to the treatment of diseases, conditions, and disorders.
  • the invention provides such combination treatments.
  • the invention provides a combination therapy comprising (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, and (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof (i.e., tucatinib or a salt thereof).
  • HER2 human epidermal growth factor receptor type 2
  • the invention also provides a pharmaceutical composition comprising (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier [0009]
  • the invention further provides a method for treating cancer in a subject comprising administering (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and
  • FIG. 1 is an illustration depicting a possible mechanism of action for BDC-1001.
  • BDC-1001 may bind HER2 expressing tumor cells via the antibody variable region.
  • myeloid cells bind to the Fc portion of the BDC-1001 through their Fc receptors leading to phagocytosis of the tumor cell/BDC-1001 complex.
  • the immune- stimulating TLR7/8 agonist attached to BDC-1001 activates myeloid antigen presenting cells (APC)s such as macrophages and dendritic cells which may lead to increased cytotoxicity, processing, and presentation of tumor neoantigens that subsequently stimulate T cell- mediated anti-tumor immune response.
  • APC myeloid antigen presenting cells
  • 2A-2D are graphs showing the percentage of tumor growth inhibition (% TGI) in human tumor xenografts using the indicated tumor cell lines following treatment with (i) trastuzumab, (ii) the combination of trastuzumab and tucatinib, (iii) BDC-1001.S, and (iv) the combination of BDC-1001.S and tucatinib.
  • the % TGI for NCI-H2170 (HER2+ IHC 2+) are set forth in FIG. 2B.
  • the % TGI for JIMT-1 (HER2+ IHC2+) are set forth in FIG. 2C.
  • the % TGI for the HCC1954 (HER2+ IHC3+) are set forth in FIG. 2D.
  • the data set forth in FIGs. 2B-2D were analyzed by ordinary one-way ANOVA, where pval ⁇ 0.05, and the % TGI results for all 3 tumor models and all four treatments are set forth in FIG. 2 A.
  • FIG. 3 is a graph showing the BDC-1001 activity in humans as determined by a human myeloid APC tumor co-culture assay.
  • BDC-1001 (closed squares) elicits enhanced myeloid activation as defined by increased secretion of TNFa relative to (a) trastuzumab (closed circles) and (b) the mixture of trastuzumab and the molar equivalent of therapeutic agent (closed triangles, “Trastuzumab + Al 03”) when myeloid cells are co-cultured with HER2-expressing tumor cells, as described in Example 2.
  • the data set forth in FIG. 3 were analyzed by ordinary one-way ANOVA, where p ⁇ 0.0001 (****) and p ⁇ 0.01 (**).
  • FIG. 4 is a graph showing the BDC-1001.S murine activity as determined by a RAW 264.7 mouse macrophage tumor co-culture assay.
  • BDC-1001. S (closed squares) elicits enhanced myeloid activation as defined by increased secretion of TNFa relative to trastuzumab (closed triangles) when co-cultured with HER2-expressing tumor cells, as described in Example 2.
  • the invention provides a method for treating cancer in a subject comprising administering (e.g., administering a therapeutically effective amount of) (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, and (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, to a subject having cancer.
  • administering e.g., administering a therapeutically effective amount of
  • Ab-[TA] r or a pharmaceutically acceptable salt thereof wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about
  • the combination therapy comprising the immunoconjugate and the compound of formula (I) can provide increased tumor growth inhibition (TGI), increased therapeutic benefit, or improved treatment outcome relative to either the immunoconjugate or the compound of formula (I) administered alone. Additional embodiments and benefits of the inventive methods will be apparent from the description herein.
  • immunoconjugate refers to an antibody construct that is covalently bonded to a therapeutic agent described herein.
  • the phrase “therapeutic agent” refers to a chemical moiety of formula: wherein n is from about 2 to about 25, as described herein.
  • the therapeutic agent can elicit the immune response (i.e., stimulation or suppression) while bonded to the antibody construct (e.g., as the intact immunoconjugate) or after cleavage (e.g., enzymatic cleavage) from the antibody construct following administration of an immunoconjugate to the subject.
  • the therapeutic agent can be cleaved at any location such that any component (i.e., active species) of the therapeutic agent can elicit the immune response (i.e., stimulation or suppression) following administration of an immunoconjugate to the subject.
  • the therapeutic agent can be an immune agonist or antagonist.
  • antibody construct refers to an antibody or a fusion protein comprising (i) an antigen binding domain and (ii) an Fc domain.
  • antibody refers to a polypeptide comprising an antigen binding region (including the complementarity determining region (CDRs)) from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen.
  • CDRs complementarity determining region
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa) connected by disulfide bonds.
  • Each chain is composed of structural domains, which are referred to as immunoglobulin domains. These domains are classified into different categories by size and function, e.g., variable domains or regions on the light and heavy chains (VL and VH, respectively) and constant domains or regions on the light and heavy chains (CL and CH, respectively).
  • the N terminus of each chain defines a variable region of about 100 to 110 or more amino acids, referred to as the paratope, primarily responsible for antigen recognition, i.e., the antigen binding domain.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • IgG antibodies are large molecules of about 150 kDa composed of four peptide chains.
  • IgG antibodies contain two identical class y heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to each other and to a light chain each by disulfide bonds. The resulting tetramer has two identical halves, which together form the Y-like shape.
  • Each end of the fork contains an identical antigen binding domain.
  • IgG subclasses IgGl, IgG2, IgG3, and IgG4
  • IgGl is the most abundant
  • the antigen binding domain of an antibody will be most critical in specificity and affinity of binding to cancer cells.
  • Antibodies can exist as intact immunoglobulins or as a number of well- characterized fragments produced by digestion with various peptidases.
  • pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
  • the F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into a Fab' monomer.
  • the Fab' monomer is essentially Fab with part of the hinge region (see, e.g., Fundamental Immunology (Paul, editor, 7th edition, 2012)). While various antibody fragments are defined in terms of the digestion of an intact antibody, such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv), or those identified using phage display libraries (see, e.g., McCafferty et al., Nature, 348: 552-554 (1990)).
  • antibody specifically encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity.
  • An antibody that targets a particular antigen includes a bispecific or multispecific antibody with at least one antigen binding region that targets the particular antigen.
  • epitope means any antigenic determinant or epitopic determinant of an antigen to which an antigen binding domain binds (i.e., at the paratope of the antigen binding domain).
  • Antigenic determinants usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and usually have specific three dimensional structural characteristics, as well as specific charge characteristics.
  • HER2 refers to the protein human epidermal growth factor receptor 2 (SEQ ID NO: 1), or an antigen with least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more sequence identity to SEQ ID NO: 1.
  • Percent (%) identity of sequences can be calculated, for example, as 100 x [(identical positions)/min(TGA, TGB)], where TGA and TGB are the sum of the number of residues and internal gap positions in peptide sequences A and B in the alignment that minimizes TGA and TGB. See, e.g., Russell et al., J. Mol Biol., 244: 332-350 (1994).
  • TLR Toll-like receptor
  • TLR polypeptides share a characteristic structure that includes an extracellular domain that has leucine-rich repeats, a transmembrane domain, and an intracellular domain that is involved in TLR signaling.
  • Toll-like receptor 7 and “TLR7” refer to nucleic acids or polypeptides sharing at least about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more sequence identity to a publicly-available TLR7 sequence, e.g., GenBank accession number AAZ99026 for human TLR7 polypeptide, or GenBank accession number AAK62676 for murine TLR7 polypeptide.
  • Toll-like receptor 8 and “TLR8” refer to nucleic acids or polypeptides sharing at least about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more sequence identity to a publicly-available TLR7 sequence, e.g., GenBank accession number AAZ95441 for human TLR8 polypeptide, or GenBank accession number AAK62677 for murine TLR8 polypeptide.
  • a “TLR agonist” is a substance that binds, directly or indirectly, to a TLR (e.g., TLR7 and/or TLR8) to induce TLR signaling. Any detectable difference in TLR signaling can indicate that an agonist stimulates or activates a TLR.
  • Signaling differences can be manifested, for example, as changes in the expression of target genes, in the phosphorylation of signal transduction components, in the intracellular localization of downstream elements such as nuclear factor-xB (NF-KB), in the association of certain components (such as IL-1 receptor associated kinase (IRAK)) with other proteins or intracellular structures, or in the biochemical activity of components such as kinases (such as mitogen-activated protein kinase (MAPK)).
  • NF-KB nuclear factor-xB
  • IRAK IL-1 receptor associated kinase
  • MAPK mitogen-activated protein kinase
  • “Ab” of the immunoconjugates refers to an antibody construct that has an antigen binding domain that binds HER2 (e.g., trastuzumab (commercially available as HERCEPTINTM), a biosimilar thereof, or a biobetter thereof.
  • HER2 e.g., trastuzumab (commercially available as HERCEPTINTM)
  • trastuzumab commercially available as HERCEPTINTM
  • biosimilar refers to an antibody construct that has active properties similar to the antibody construct previously approved (e.g., trastuzumab).
  • biobetter refers to an approved antibody construct that is an improvement of a previously approved antibody construct (e.g., trastuzumab). The biobetter can have one or more modifications (e.g., an altered glycan profile, or a unique epitope) over the previously approved antibody construct.
  • amino acid refers to any monomeric unit that can be incorporated into a peptide, polypeptide, or protein.
  • Amino acids include naturally-occurring a-amino acids and their stereoisomers, as well as unnatural (non-naturally occurring) amino acids and their stereoisomers.
  • “Stereoisomers” of a given amino acid refer to isomers having the same molecular formula and intramolecular bonds but different three-dimensional arrangements of bonds and atoms (e.g., an L-amino acid and the corresponding D-amino acid).
  • amino acids can be glycosylated (e.g., TV-linked glycans, O-linked glycans, phosphoglycans, C-linked glycans, or glypiation) or deglycosylated.
  • Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxy glutamate, and O-phosphoserine.
  • Naturally-occurring a-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (He), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gin), serine (Ser), threonine (Thr), valine (Vai), tryptophan (Trp), tyrosine (Tyr), and combinations thereof.
  • Stereoisomers of naturally-occurring a-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D- histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D- Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D- Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D- tyrosine (D-Tyr), and combinations thereof.
  • D-Ala
  • Unnatural (non-naturally occurring) amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, TV-substituted glycines, and N-m ethyl amino acids in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids.
  • amino acid analogs can be unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids (i.e., a carbon that is bonded to a hydrogen, a carboxyl group, or an amino group) but have modified side-chain groups or modified peptide backbones, e.g., homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium.
  • Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally-occurring amino acid.
  • Amino acids may be referred to herein by either the commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • the terms “treat,” “treatment,” and “treating” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition (e.g., cancer), or symptom (e.g., cognitive impairment), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology, or condition more tolerable to the subject; reduction in the rate of symptom progression; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the result of a physical examination.
  • the treatment or amelioration of symptoms could be considered the standard of care at the time of treatment and/or consistent with the current practices in neoadjuvant, adjuvant, l st -line (IL), 2 nd -line (2L), 3 rd -line (3L), 4 th -line (4L), 5 th -line (5L), 6 th -line (6L), 7'Mine (7L), and beyond treatments for the cancer being treated.
  • the treatment or amelioration of symptoms may be used with any type of tumor at any stage of disease.
  • cancer refers to cells which exhibit autonomous, unregulated growth, such that the cells exhibit an aberrant growth phenotype characterized by a significant loss of control over cell proliferation.
  • Cells of interest for detection, analysis, and/or treatment in the context of the invention include cancer cells (e.g., cancer cells from an individual with cancer), malignant cancer cells, pre-metastatic cancer cells, metastatic cancer cells, and non-metastatic cancer cells. Cancers of virtually every tissue are known.
  • cancer burden refers to the quantum of cancer cells or cancer volume in a subject. Reducing cancer burden accordingly refers to reducing the number of cancer cells or the cancer cell volume in a subject.
  • cancer cell refers to any cell that is a cancer cell (e.g., from any of the cancers for which an individual can be treated, e.g., isolated from an individual having cancer) or is derived from a cancer cell, e.g., clone of a cancer cell.
  • a cancer cell can be from an established cancer cell line, can be a primary cell isolated from an individual with cancer, can be a progeny cell from a primary cell isolated from an individual with cancer, and the like.
  • the term can also refer to a portion of a cancer cell, such as a sub-cellular portion, a cell membrane portion, or a cell lysate of a cancer cell.
  • cancers are known to those of skill in the art, including solid tumors such as carcinomas, sarcomas, glioblastomas, melanomas, lymphomas, and plasmacytomas, and circulating cancers such as leukemias.
  • solid tumors such as carcinomas, sarcomas, glioblastomas, melanomas, lymphomas, and plasmacytomas
  • circulating cancers such as leukemias.
  • cancer includes any form of cancer, including but not limited to, solid tumor cancers (e.g., lung, prostate, breast, gastric, bladder, colorectal (i.e., colon and/or rectal), ovarian, pancreas, kidney, biliary (e.g., liver, gall bladder, or bile duct), glioblastoma, medulloblastoma, leiomyosarcoma, head & neck squamous cell carcinomas, melanomas, urothelial, bladder, cervical, endometrial, salivary gland, and neuroendocrine) and liquid cancers (e.g., hematological cancers); carcinomas; soft tissue tumors; sarcomas; teratomas; melanomas; leukemias; lymphomas; and brain cancers, including minimal residual disease, and including both primary and metastatic tumors.
  • solid tumor cancers e.g., lung, prostate, breast, gastric, bladder, colorectal (i
  • Carcinomas are malignancies that originate in the epithelial tissues. Epithelial cells cover the external surface of the body, line the internal cavities, and form the lining of glandular tissues.
  • carcinomas include, but are not limited to, adenocarcinoma (cancer that begins in glandular (secretory) cells such as cancers of the breast, pancreas, lung, prostate, stomach, esophageal (e.g., gastroesophageal junction), salivary gland, and colon), adrenocortical carcinoma; hepatocellular carcinoma; renal cell carcinoma; ovarian carcinoma; carcinoma in situ; ductal carcinoma; carcinoma of the breast; basal cell carcinoma; squamous cell carcinoma; transitional cell carcinoma; colon carcinoma; nasopharyngeal carcinoma; multilocular cystic renal cell carcinoma; oat cell carcinoma (i.e., small cell lung carcinoma); large cell lung carcinoma; small cell lung carcinoma; non-small cell lung carcinoma; and the like. Carcinomas may be found in prosta, tub
  • Soft tissue tumors are a highly diverse group of rare tumors that are derived from connective tissue.
  • soft tissue tumors include, but are not limited to, alveolar soft part sarcoma; angiomatoid fibrous histiocytoma; chondromyoxid fibroma; skeletal chondrosarcoma; extraskeletal myxoid chondrosarcoma; clear cell sarcoma; desmoplastic small round-cell tumor; dermatofibrosarcoma protuberans; endometrial stromal tumor; Ewing’s sarcoma; fibromatosis (Desmoid); fibrosarcoma, infantile; gastrointestinal stromal tumor; bone giant cell tumor; tenosynovial giant cell tumor; inflammatory myofibroblastic tumor; uterine leiomyoma; leiomyosarcoma; lipoblastoma; typical lipoma; spindle cell or pleomorphic lipoma; a
  • a sarcoma is a rare type of cancer that arises in cells of mesenchymal origin, e.g., in bone or in the soft tissues of the body, including cartilage, fat, muscle, blood vessels, fibrous tissue, or other connective or supportive tissue.
  • Different types of sarcoma are based on where the cancer forms. For example, osteosarcoma forms in bone, liposarcoma forms in fat, and rhabdomyosarcoma forms in muscle.
  • sarcomas include, but are not limited to, angiosarcoma, Askin’s tumor; sarcoma botryoides; chondrosarcoma; Ewing’s sarcoma; malignant hemangioendothelioma; malignant schwannoma; osteosarcoma; and soft tissue sarcomas (e.g., alveolar soft part sarcoma; angiosarcoma; cystosarcoma phyllodes, dermatofibrosarcoma protuberans (DFSP); desmoid tumor; desmoplastic small round cell tumor; epithelioid sarcoma; extraskeletal chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; gastrointestinal stromal tumor (GIST); hemangiopericytoma; hemangiosarcoma (more commonly referred to as “angiosarcoma”); Kaposi’s sarcoma; leiomyosar
  • a teratoma is a type of germ cell tumor that may contain several different types of tissue (e.g., can include tissues derived from any and/or all of the three germ layers: endoderm, mesoderm, and ectoderm), including, for example, hair, muscle, and bone.
  • tissue e.g., can include tissues derived from any and/or all of the three germ layers: endoderm, mesoderm, and ectoderm, including, for example, hair, muscle, and bone.
  • Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children.
  • Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). Melanoma may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines.
  • Leukemias are cancers that start in blood-forming tissue, such as the bone marrow, and cause large numbers of abnormal blood cells to be produced and enter the bloodstream.
  • leukemias can originate in bone marrow-derived cells that normally mature in the bloodstream.
  • Leukemias are named for how quickly the disease develops and progresses (e.g., acute versus chronic) and for the type of white blood cell that is affected (e.g., myeloid versus lymphoid).
  • Myeloid leukemias are also called myelogenous or myeloblastic leukemias.
  • Lymphoid leukemias are also called lymphoblastic or lymphocytic leukemia.
  • Lymphoid leukemia cells may collect in the lymph nodes, which can become swollen.
  • leukemias include, but are not limited to, Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL), Chronic myeloid leukemia (CML), and Chronic lymphocytic leukemia (CLL).
  • Lymphomas are cancers that begin in cells of the immune system.
  • lymphomas can originate in bone marrow-derived cells that normally mature in the lymphatic system.
  • One category of lymphoma is Hodgkin lymphoma (HL), which is marked by the presence of a type of cell called the Reed- Sternberg cell.
  • HL Hodgkin lymphoma
  • Examples of Hodgkin lymphomas include nodular sclerosis classical Hodgkin lymphoma (CEIL), mixed cellularity CHL, lymphocyte-depletion CHL, lymphocyte-rich CHL, and nodular lymphocyte predominant HL.
  • CEIL Hodgkin lymphoma
  • NHL non-Hodgkin lymphomas
  • non-Hodgkin lymphomas include, but are not limited to, AIDS-related Lymphomas, anaplastic large-cell lymphoma, angioimmunoblastic lymphoma, blastic NK- cell lymphoma, Burkitt’s lymphoma, Burkitt-like lymphoma (small non-cleaved cell lymphoma), chronic lymphocytic leukemia/small lymphocytic lymphoma, cutaneous T-Cell lymphoma, diffuse large B-Cell lymphoma, enteropathy-type T-Cell lymphoma, follicular lymphoma, hepatosplenic gamma-delta T-Cell lymphomas, T-Cell leukemias, lymphoblastic lymphoma, mantle cell lymphoma, marginal zone lymphoma, nasal T-Cell lymphoma, pediatric lymphoma, peripheral T-Cell lymphomas, primary central nervous system lymphoma, transformed lymphomas
  • Brain cancers include any cancer of the brain tissues.
  • Examples of brain cancers include, but are not limited to, gliomas (e.g., glioblastomas, astrocytomas, oligodendrogliomas, ependymomas, and the like), meningiomas, pituitary adenomas, and vestibular schwannomas, primitive neuroectodermal tumors (medulloblastomas).
  • the “pathology” of cancer includes all phenomena that compromise the wellbeing of the subject. This includes, without limitation, abnormal or uncontrollable cell growth, metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or aggravation of inflammatory or immunological response, neoplasia, premalignancy, malignancy, and invasion of surrounding or distant tissues or organs, such as lymph nodes.
  • cancer recurrence refers to further growth of neoplastic or cancerous cells after diagnosis of cancer. Particularly, recurrence may occur when further cancerous cell growth occurs in the cancerous tissue.
  • Tuor spread similarly, occurs when the cells of a tumor disseminate into local or distant tissues and organs, therefore, tumor spread encompasses tumor metastasis.
  • Tuor invasion occurs when the tumor growth spread out locally to compromise the function of involved tissues by compression, destruction, or prevention of normal organ function.
  • metastasis refers to the growth of a cancerous tumor in an organ or body part, which is not directly connected to the organ of the original cancerous tumor. Metastasis will be understood to include micrometastasis, which is the presence of undetectable cancerous cells in an organ or body part that is not directly connected to the organ of the original cancerous tumor. Metastasis can also be defined as several steps of a process, such as the departure of cancer cells from an original tumor site, and migration and/or invasion of cancer cells to other parts of the body.
  • the phrases “effective amount” and “therapeutically effective amount” refer to a dose of a substance such as an immunoconjugate and/or tucatinib that produces therapeutic effects for which it is administered.
  • the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.
  • the terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired (e.g., humans).
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, camels, etc. In certain embodiments, the mammal is human.
  • the phrase “synergistic therapeutic agent” or “synergistic combination” in the context of this invention includes the combination of two immune modulators such as a receptor agonist, cytokine, adjuvant small molecule, and adjuvant polypeptide, that in combination elicit an improved (e.g., synergistic) effect on immunity relative to either administered alone.
  • the combination therapies disclosed herein can comprise synergistic combinations of the immunoconjugate and the compound of Formula (I), i.e., tucatinib.
  • This synergistic combination upon administration elicits a greater effect on immunity, e.g., relative to when the immunoconjugate is administered in the absence of the compound of Formula (I), i.e., tucatinib.
  • a decreased amount of the immunoconjugate may be administered (as measured by the total number of antibody constructs or the total number of therapeutic agents administered as part of the immunoconjugate) compared to when either the immunoconjugate, the antibody construct, or therapeutic agent is administered alone.
  • administering refers to parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration (i.e., orally), administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to the subject.
  • a slow-release device e.g., a mini-osmotic pump
  • the abbreviation “AUC” refers to “area under the curve” and can be determined using biological samples analyzed with LC/MS/MS. Accordingly, the AUC can be determined by any suitable LC/MS/MS apparatus.
  • the AUC can be calculated from a single exposure, multi-dose, and/or a steady state exposure curve. Alternatively, or in addition to, the AUC can be calculated from the average (mean), time-weighted average, and/or instantaneous drug exposure curve. Typically, the AUC refers to the average area under the curve for a single dose drug exposure over a period of 24 hours.
  • the phrase “coefficient of variation” refers to the relative standard deviation and is calculated as follows: wherein Cvis the coefficient of variation, a is the standard deviation, and p is the mean. [0058] As used herein, the abbreviation “Cmax” refers to the maximum plasma concentration.
  • ti/2 refers to the biological half-life.
  • the invention provides a combination therapy comprising (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, as described herein, and (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, i.e., tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof.
  • the combination therapy can be for use as a medicament for treating cancer in a subject having cancer in accordance with any embodiment described herein.
  • the term “combination therapy” refers to a treatment protocol comprising administration of both an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, and tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof.
  • the immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, and tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof, can be administered simultaneously (i.e., as a single composition), concurrently (i.e., as two separate compositions administered at the same time), intermittently (i.e., as needed to fulfill the dosing regimen of each of the immunoconjugate and tucatinib individually), or sequentially (i.e., one treatment followed (e.g., within 1 week, within 3 days, within 1 day, within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, or immediately) by the other treatment) in accordance with the dosing regimens described herein.
  • the method includes treating cancer in a subject comprising administering (e.g., administering a therapeutically effective amount of) the immunoconjugate, or a pharmaceutically acceptable salt thereof.
  • the method can include treating cancer in a subject comprising administering from about 0.01 mg/kg to about 100 mg/kg of the immunoconjugate, or a pharmaceutically acceptable salt thereof, to the subject.
  • the method can include administering the immunoconjugate, or pharmaceutically acceptable salt thereof, to provide a dose of from about 0.1 mg/kg to about 90 mg/kg, from about 0.1 mg/kg to about 80 mg/kg, from about 0.1 mg/kg to about 70 mg/kg, from about 0.1 mg/kg to about 60 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.1 mg/kg to about 30 mg/kg, from about 0.1 mg/kg to about 25 mg/kg, from about 0.1 mg/kg to about 0.2 mg/kg, from about 0.25 mg/kg to 0.75 about mg/kg, from about 1 mg/kg to about 3 mg/kg, from about 4 mg/kg to about 6 mg/kg, from about 4.5 mg/kg to about 5.5 mg/kg, from about 8 mg/kg to about 12 mg/kg, from about 9 mg/kg to about 11 mg/kg, from about 10 mg/kg to about 14 mg/kg, from about 11 mg
  • the method include administering about 0.15 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, or about 30 mg/kg of the immunoconjugate, or a pharmaceutically acceptable salt thereof, to the subject.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof is administered from about every 3 to about every 45 days (e.g., about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 days, about every 9 days, about every 10 days, about every 11 days, about every 12 days, about every 13 days, about every 14 days, about every 15 days, about every 16 days, about every 17 days, about every 18 days, about every 19 days, about every 20 days, about every 21 days, about every 22 days, about every 23 days, about every 24 days, about every 25 days, about every 26 days, about every 27 days, about every 28 days, about every 29 days, about every 30 days, about every 31 days, about every 32 days, about every 33 days, about every 34 days, about every 35 days, about every 36 days, about every 37 days, about every 38 days, about every 39 days, about every 40 days, about every 41 days, about every 42 days, about every 43 days, about every 44 days, or about every 45 days (e.g., about every
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof is administered from about every 3 to about every 35 days. In some embodiments, the immunoconjugate, or a pharmaceutically acceptable salt thereof, is administered every 1, 2, 3, 4, 5, 6, or 7 weeks, or every month. In some embodiments, the immunoconjugate, or a pharmaceutically acceptable salt thereof, is administered from about every 5 to about every 9 days, from about every 6 to about every 8 days, from about every 13 to about every 15 days, from about every 12 to about every 16 days, from about every 20 to about every 22 days, from about every 19 to about every 23 days, from about every 27 to about every 29 days, from about every 26 to about every 30 days, or from about every 33 to about every 37 days. In some embodiments, the immunoconjugate, or a pharmaceutically acceptable salt thereof, is administered about every 7 days, about every about 14 days, about every 21 days, about every 28 days, about every 35 days, or about every 42 days.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject as an initial loading dose followed by one or more maintenance doses.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered as a loading dose to the subject at about 5 mg/kg, about 8 mg/kg, about 12 mg/kg, about 15 mg/kg, or about 20 mg/kg by IV infusion.
  • the loading dose may be a higher or lower dose than the one or more maintenance doses.
  • the loading dose may be administered to the patient using a similar or different suitable means than the one or more maintenance doses.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject using any suitable means including parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration (i.e., orally), administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow release device, e.g., a miniosmotic pump, to the subject.
  • a slow release device e.g., a miniosmotic pump
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof is administered subcutaneously.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof is administered intravenously (e.g., IV infusion). In some embodiments, the immunoconjugate, or a pharmaceutically acceptable salt thereof, is administered to the subject intravenously over about 1 to about 240 minutes.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered over about 5 to about 55 minutes, over about 10 to about 50 minutes, over about 15 to about 45 minutes, over about 20 to about 40 minutes, over about 25 to about 35 minutes, over about 30 minutes to the subject, over about 30 to about 90 minutes, over about 35 to about 85 minutes, over about 40 to about 80 minutes, over about 45 to about 75 minutes, over about 50 to about 70 minutes, over about 55 to about 65 minutes, over about 60 minutes, over about 90 to about 150 minutes, over about 95 to about 145 minutes, over about 100 to about 140 minutes, over about 105 to about 135 minutes, over about 110 to about 130 minutes, over about 115 to about 125 minutes, over about 120 minutes, over about 150 to about 210 minutes, over about 155 to about 205 minutes, over about 160 to about 200 minutes, over about 165 to about 195 minutes, over about 170 to about 190 minutes, over about 175 to about 185 minutes, over about 180 minutes, over about 210 to about 270 minutes, over about
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject for any suitable length of time.
  • the immunoconjugate, or pharmaceutically acceptable salt thereof can be administered to the subject one time or multiple times. If the immunoconjugate, or pharmaceutically acceptable salt thereof, is administered multiple times, the immunoconjugate, or a pharmaceutically acceptable salt thereof, can be administered for a duration of from about 1 month to about 48 months (e.g., from about 1 to about 45 months, from about 1 to about 40 months, from about 1 to about 35 months, from about 1 to about 30 months, from about 1 to about 25 months, from about 1 to about 20 months, from about 1 to about 15 months, from about 1 to about 12 months, from about 1 to about 10 months, from about 1 to about 5 months, from about 1 to about 4 months, from about 1 to about 3 months, from about 1 to about 2 months, or about 1 month).
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.15 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.5 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 2 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 5 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 8 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 12 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 20 mg/kg every week by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.15 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.5 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 2 mg/kg every
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 5 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 8 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 12 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 20 mg/kg every 2 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.15 mg/kg every 3 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 0.5 mg/kg every 3 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 2 mg/kg every
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 5 mg/kg every 3 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 8 mg/kg every 3 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 12 mg/kg every 3 weeks by IV infusion.
  • the immunoconjugate, or a pharmaceutically acceptable salt thereof can be administered to the subject at 20 mg/kg every 3 weeks by IV infusion.
  • the invention provides an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2) and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 (e.g., about 2 to about 16, about 6 to about 25, about 6 to about 16, about 8 to about 25, about 8 to about 16, about 6 to about 12, about 8 to about 12, or about 10), and r is an average therapeutic agent to antibody ratio from 1 to 10.
  • “Ab” can be any suitable antibody construct that has an antigen binding domain that binds HER2, such as, for example, trastuzumab and pertuzumab.
  • “Ab” is trastuzumab (commercially available as HERCEPTINTM), a biosimilar thereof, or a biobetter thereof
  • “Ab” can be MYL-14010, ABP 980, BCD-022, CT-P6, EG12014, HD201, ONS-1050, PF-05280014, ONTRUZANTTM (SB3), Saiputing, HERZUMATM (CT- P6), or HLX02.
  • “Ab” is trastuzumab (commercially available as HERCEPTINTM).
  • the immunoconjugates of the invention have an average therapeutic agent to antibody ratio of from 1 to 10.
  • the average therapeutic agent to antibody is designated with subscript “r ”
  • each of the therapeutic agents is conjugated to the antibody construct at an amine of a lysine residue of the antibody construct.
  • r is 1, such that there is only one therapeutic agent bound to the antibody construct (i.e., a homogenous conjugation of one).
  • r is any number from about 1 to about 10 (e.g., about 2 to about 10, about 2 to about 9, about 3 to about 9, about 4 to about 9, about 5 to about 9, about 6 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 5 to about 6, about 1 to about 6, about 1 to about 4, about 2 to about 4, or about 1 to about 3).
  • the immunoconjugates have an average therapeutic agent to antibody construct ratio (i.e., subscript “r” can be) from about 1 to about 4 or about 2 to about 3.
  • the desirable average therapeutic agent to antibody construct ratio i.e., the value of the subscript “r” can be determined by a skilled artisan depending on the desired effect of the treatment.
  • the immunoconjugates of the invention comprise about 2 to about 25 (e.g., about 2 to about 16, about 6 to about 25, about 6 to about 16, about 8 to about 25, about 8 to about 16, about 6 to about 12, or about 8 to about 12) ethylene glycol units in the therapeutic agent, as designated with subscript “n.”
  • the immunoconjugates of the invention can comprise at least 2 ethylene glycol groups (e.g., at least 3 ethylene glycol groups, at least 4 ethylene glycol groups, at least 5 ethylene glycol groups, at least 6 ethylene glycol groups, at least 7 ethylene glycol groups, at least 8 ethylene glycol groups, at least 9 ethylene glycol groups, or at least 10 ethylene glycol groups).
  • the immunoconjugate can comprise from about 2 to about 25 ethylene glycol units in the therapeutic agent, for example, from about 6 to about 25 ethylene glycol units, from about 6 to about 16 ethylene glycol units, from about 8 to about 25 ethylene glycol units, from about 8 to about 16 ethylene glycol units, from about 8 to about 12 ethylene glycol units, or from about 8 to about 12 ethylene glycol units.
  • the immunoconjugate comprises a di(ethylene glycol) group, a tri(ethylene glycol) group, a tetra(ethylene glycol) group, 5 ethylene glycol groups, 6 ethylene glycol groups, 7 ethylene glycol groups, 8 ethylene glycol groups, 9 ethylene glycol groups, 10 ethylene glycol groups, 11 ethylene glycol groups, 12 ethylene glycol groups, 13 ethylene glycol groups, 14 ethylene glycol groups, 15 ethylene glycol groups, 16 ethylene glycol groups, 24 ethylene glycol groups, or 25 ethylene glycol groups.
  • the immunoconjugate comprises 6 ethylene glycol groups, 8 ethylene glycol groups, 10 ethylene glycol groups, or 12 ethylene glycol groups (i.e., about 6 ethylene glycol groups to about 12 ethylene glycol groups) in the therapeutic agent.
  • the therapeutic agent can be conjugated to the antibody construct that has an antigen binding domain that binds HER2 (e.g., trastuzumab, pertuzumab, biosimilars thereof, and biobetters thereof) via an amine of a lysine residue of the antibody construct.
  • HER2 e.g., trastuzumab, pertuzumab, biosimilars thereof, and biobetters thereof
  • the immunoconjugates of the invention can be represented by the following formula:
  • the therapeutic agent can be bound to any suitable residue of the antibody construct, but desirably is bound to any lysine residue of the antibody construct.
  • the therapeutic agent can be bound to one or more of KI 03, KI 07, KI 49, KI 69, KI 83, and/or KI 88 of the light chain of the antibody construct, as numbered using the Kabat numbering system.
  • the therapeutic agent can be bound to one or more of K30, K43, K65, K76, K136, K216, K217, K225, K293, K320, K323, K337, K395, and/or K417 of the heavy chain of the antibody construct, as numbered using the Kabat numbering system.
  • the therapeutic agent is predominantly bound at KI 07 or K188 of the light chain of the antibody construct, or K30, K43, K65, or K417 of the heavy chain of the antibody construct. In certain embodiments, the therapeutic agent is bound at KI 88 of the light chain of the antibody construct, and optionally one or more other lysine residues of the antibody construct.
  • An immunoconjugate, or a pharmaceutically acceptable salt thereof, as described herein can provide an unexpectedly increased activation response of an antigen presenting cell (APC).
  • APC antigen presenting cell
  • This increased activation can be detected in vitro or in vivo.
  • the increased APC activation can be detected in the form of a reduced time to achieve a specified level of APC activation.
  • % APC activation can be achieved at an equivalent dose with an immunoconjugate within about 1%, about 10%, about 20%, about 30%, about 40%, or about 50% of the time required to obtain the same or similar percentage of APC activation with a mixture of unconjugated antibody construct and therapeutic agent, under otherwise identical concentrations and conditions.
  • an immunoconjugate can activate APCs (e.g., dendritic cells) and/or NK cells in a reduced amount of time.
  • APCs e.g., dendritic cells
  • a mixture of unconjugated antibody construct and therapeutic agent can activate APCs (e.g., dendritic cells) and/or NK cells and/or induce dendritic cell differentiation after incubation with the mixture for 2, 3, 4, 5, 1-5, 2-5, 3-5, or 4-7 days, while, in contrast, immunoconjugates described herein can activate and/or induce differentiation within 4 hours, 8 hours, 12 hours, 16 hours, or 1 day, under otherwise identical concentrations and conditions.
  • the increased APC activation can be detected in the form of a reduced concentration of immunoconjugate required to achieve an amount (e.g., percent APCs), level (e.g., as measured by a level of upregulation of a suitable marker) or rate (e.g., as detected by a time of incubation required to activate) of APC activation.
  • an amount e.g., percent APCs
  • level e.g., as measured by a level of upregulation of a suitable marker
  • rate e.g., as detected by a time of incubation required to activate
  • the immunoconjugates of the invention provide more than an about 5% increase in activity compared to a mixture of unconjugated antibody construct and therapeutic agent, under otherwise identical conditions. In other embodiments, the immunoconjugates of the invention provide more than an about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% increase in activity compared to a mixture of unconjugated antibody construct and therapeutic agent, under otherwise identical conditions.
  • the increase in activity can be assessed by any suitable means, many of which are known to those ordinarily skilled in the art and can include myeloid activation, assessment by cytokine secretion, or a combination thereof.
  • the invention provides an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2) and “TA” is a therapeutic agent of formula:
  • the invention provides an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is trastuzumab (commercially available as HERCEPTINTM), pertuzumab, a biosimilar thereof, or a biobetter thereof (for example, “Ab” can be MYL-14010, ABP 980, BCD-022, CT-P6, EG12014, HD201, ONS-1050, PF-05280014, ONTRUZANTTM (SB3), Saiputing, HERZUMATM (CT- P6), or HLX02) and “TA” is a therapeutic agent of formula:
  • the invention provides an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is trastuzumab (commercially available as HERCEPTINTM) and “TA” is a therapeutic agent of formula:
  • the invention provides an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is trastuzumab (commercially available as HERCEPTINTM) and “TA” is a therapeutic agent of formula: wherein subscript r is an average therapeutic agent to antibody ratio from about 1 to about 10.
  • This immunoconjugate is referred to herein as BDC-1001.
  • an immunoconjugate such as BDC-1001 binds to HER2 expressing tumor cells via the “Ab” of BDC-1001 leading to tumor cell killing and phagocytosis.
  • the therapeutic agent of BDC- 1001 activates myeloid APCs such as macrophages and dendritic cells which leads to increased cytotoxicity, processing, and presentation of tumor neoantigens that subsequently stimulate T cell-mediated immunity (see FIG. 1).
  • administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof results in increased plasma levels of cytokines and/or chemokines, such as those consistent with TLR7/8 and myeloid cell activation.
  • administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof results in increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) in the subject.
  • administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof results in increased plasma levels of macrophage inflammatory protein la (MIPla) in the subject.
  • administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof results in increased plasma levels of interferon gamma-induced protein 10 (IP-10) in the subject.
  • IP-10 interferon gamma-induced protein 10
  • administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof results in increased plasma levels of indicators of TLR activation. In some embodiments, administration of the immunoconjugate, or a pharmaceutically acceptable salt thereof, results in increased plasma levels of TNFa.
  • the immunoconjugate of the invention comprises a therapeutic agent of formula: wherein n is from about 2 to about 25 and represents a point of attachment of the therapeutic agent to the antibody construct.
  • the therapeutic agent described herein is an adjuvant, more specifically, is a TLR agonist.
  • the cancer treated by the method of the invention is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism.
  • the immunoconjugates of the invention comprise an antibody construct that comprises an antigen binding domain that binds HER2.
  • the antibody construct further comprises an Fc domain.
  • the antibody construct is an antibody.
  • the antibody construct is a fusion protein.
  • the antigen binding domain can be a single-chain variable region fragment (scFv).
  • scFv single-chain variable region fragment
  • dsFv disulfide-stabilized variable region fragments
  • An embodiment of the invention provides antibody construct or antigen binding domain which specifically recognizes and binds to HER2 (SEQ ID NO: 1).
  • the antibody construct or antigen binding domain may comprise one or more variable regions (e.g., two variable regions) of an antigen binding domain of an anti-HER2 antibody, each variable region comprising a CDR1, a CDR2, and a CDR3.
  • an embodiment of the invention provides an antibody construct or antigen binding domain comprising the CDR regions of trastuzumab.
  • the antigen binding domain may comprise a first variable region comprising light chain complementary determining region-1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 2 (CDRL1 of first variable region), a light chain complementary determining region-2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 3 (CDRL2 of first variable region), and a light chain complementary determining region-3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 4 (CDRL3 of first variable region), and a second variable region comprising a heavy chain complementary determining region-1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 5 (CDRH1 of second variable region), a heavy chain complementary determining region-2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 6 (CDRH2 of second variable region), and a heavy chain complementary determining region-3 (CDRH3) comprising the amino
  • the antibody construct can comprise (i) all of SEQ ID NOs: 2-4, (ii) all of SEQ ID NOs: 5-7, or (iii) all of SEQ ID NOs: 2-7.
  • the antigen binding domain comprises all of SEQ ID NOs: 2-7.
  • the antigen binding domain comprising the CDR regions of trastuzumab further comprises the framework regions of the trastuzumab.
  • the antigen binding domain comprising the CDR regions of trastuzumab further comprises the amino acid sequence of SEQ ID NO: 8 (framework region (FR) 1 of first variable region), the amino acid sequence of SEQ ID NO: 9 (FR2 of first variable region), the amino acid sequence of SEQ ID NO: 10 (FR3 of first variable region), the amino acid sequence of SEQ ID NO: 11 (FR4 of first variable region), the amino acid sequence of SEQ ID NO: 12 (FR1 of second variable region), the amino acid sequence of SEQ ID NO: 13 (FR2 of second variable region), the amino acid sequence of SEQ ID NO: 14 (FR3 of second variable region), and the amino acid sequence of SEQ ID NO: 15 (FR4 of second variable region).
  • the antibody construct or antigen binding domain can comprise (i) all of SEQ ID NOs: 2-4 and 8-11, (ii) all of SEQ ID NOs: 5-7 and 12-15; or (iii) all of SEQ ID NOs: 2-7 and 8-15.
  • the antigen binding domain comprises one or both variable regions of trastuzumab.
  • the first variable region may comprise SEQ ID NO: 30.
  • the second variable region may comprise SEQ ID NO: 31.
  • the antigen binding domain comprises SEQ ID NO: 30, SEQ ID NO: 31, or both SEQ ID NOs: 30 and 31.
  • the antigen binding domain comprises both of SEQ ID NOs: 30-31.
  • the antigen binding domain comprises the CDR regions of pertuzumab.
  • the antigen binding domain may comprise a first variable region comprising a light chain complementary determining region-1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 16 (CDRL1 of first variable region), a light chain complementary determining region-2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 17 (CDRL2 of first variable region), and a light chain complementary determining region-3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 18 (CDRL3 of first variable region), and a second variable region comprising a heavy chain complementary determining region-1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 19 (CDRH1 of second variable region), a heavy chain complementary determining region-2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 20 (CDRH2 of second variable region), and a heavy chain complementary determining region-3 (CDRH3) comprising the amino acid
  • the antigen binding domain can comprise (i) all of SEQ ID NOs: 16-18, (ii) all of SEQ ID NOs: 19-21, or (iii) all of SEQ ID NOs: 16-21.
  • the antigen binding domain comprises all of SEQ ID NOs: 16-21.
  • the antigen binding domain comprising the CDR regions of pertuzumab further comprises the framework regions of the pertuzumab.
  • the antigen binding domain comprising the CDR regions of the pertuzumab further comprises the amino acid sequence of SEQ ID NO: 22 (FR1 of first variable region), the amino acid sequence of SEQ ID NO: 23 (FR2 of first variable region), the amino acid sequence of SEQ ID NO: 24 (FR3 of first variable region), the amino acid sequence of SEQ ID NO: 25 (FR4 of first variable region), the amino acid sequence of SEQ ID NO: 26 (FR1 of second variable region), the amino acid sequence of SEQ ID NO: 27 (FR2 of second variable region), the amino acid sequence of SEQ ID NO: 28 (FR3 of second variable region), and the amino acid sequence of SEQ ID NO: 29 (FR4 of second variable region).
  • the antigen binding domain can comprise (i) all of SEQ ID NOs: 16-18 and 22-25, (ii) all of SEQ ID NOs: 19-21 and 26-29; or (iii) all of SEQ ID NOs: 16-21 and 22-29.
  • the antigen binding domain comprises one or both variable regions of pertuzumab.
  • the first variable region may comprise SEQ ID NO: 32.
  • the second variable region may comprise SEQ ID NO: 33.
  • the antigen binding domain comprises SEQ ID NO: 32, SEQ ID NO: 33, or both SEQ ID NOs: 32 and 33.
  • the antigen binding domain comprises both of SEQ ID NOs: 32-33.
  • the scope of the embodiments of the invention includes functional variants of the antibody construct and antigen binding domain described herein.
  • the term “functional variant” as used herein refers to an antibody construct having an antigen binding domain with substantial or significant sequence identity or similarity to a parent antibody construct or antigen binding domain, which functional variant retains the biological activity of the parent antibody construct or antigen binding domain, respectively, of which it is a variant.
  • Functional variants encompass, for example, those variants of the antibody construct or antigen binding domain described herein (the parent antibody construct or antigen binding domain) that retain the ability to recognize target cells expressing HER2 to a similar extent, the same extent, or to a higher extent, as the parent antibody construct or antigen binding domain.
  • the functional variant can, for instance, be at least about 30%, about 50%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more identical in amino acid sequence to the parent antibody construct or antigen binding domain, respectively.
  • a functional variant can, for example, comprise the amino acid sequence of the parent antibody construct or antigen binding domain with at least one conservative amino acid substitution.
  • the functional variant can comprise the amino acid sequence of the parent antibody construct or antigen binding domain with at least one non-conservative amino acid substitution.
  • the non-conservative amino acid substitution may enhance the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the parent antibody construct or antigen binding domain, respectively.
  • Amino acid substitutions of the inventive antibody constructs or antigen binding domains are preferably conservative amino acid substitutions.
  • Conservative amino acid substitutions are known in the art and include amino acid substitutions in which one amino acid having certain physical and/or chemical properties is exchanged for another amino acid that has the same or similar chemical or physical properties.
  • the conservative amino acid substitution can be an acidic/negatively charged polar amino acid substituted for another acidic/negatively charged polar amino acid (e.g., Asp or Glu), an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side chain (e.g., Ala, Gly, Vai, He, Leu, Met, Phe, Pro, Trp, Cys, Vai, etc.), a basic/positively charged polar amino acid substituted for another basic/positively charged polar amino acid (e.g., Lys, His, Arg, etc.), an uncharged amino acid with a polar side chain substituted for another uncharged amino acid with a polar side chain (e.g., Asn, Gin, Ser, Thr, Tyr, etc.), an amino acid with a beta-branched side-chain substituted for another amino acid with a beta-branched side-chain (e.g., He, Thr, and Vai), an amino acid with an aromatic side-chain substituted
  • the antibody construct or antigen binding domain can consist essentially of the specified amino acid sequence or sequences described herein, such that other components, e.g., other amino acids, do not materially change the biological activity of the antibody construct or antigen binding domain functional variant.
  • the antibody constructs and antigen binding domains of embodiments of the invention can be of any length, i.e., can comprise any number of amino acids, provided that the antibody constructs (or functional portions or functional variants thereof) retain their biological activity, e.g., the ability to specifically bind to HER2, detect cancer cells in a mammal, or treat or prevent cancer in a mammal, etc.
  • the antibody construct or antigen binding domain can be about 50 to about 5,000 amino acids long, such as 50, 70, 75, 100, 125, 150, 175, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, or more amino acids in length.
  • the antibody constructs and antigen binding domains of embodiments of the invention can comprise synthetic amino acids in place of one or more naturally-occurring amino acids.
  • synthetic amino acids are known in the art, and include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl- cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4- nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, P-phenylserine P-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2 - carboxylic acid, l,2,3,4-tetrahydroisoquinoline-3-
  • the antibody constructs of embodiments of the invention can be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via, e.g., a disulfide bridge, or converted into an acid addition salt and/or optionally dimerized or polymerized.
  • the antibody construct is a monoclonal antibody of a defined sub-class (e.g., IgGi, IgG2, IgGs, IgG4, IgAi, or IgA?).
  • the antibody construct is an IgGi antibody.
  • a specific subclass or a specific combination of different subclasses can be particularly effective at cancer treatment or tumor size reduction. Accordingly, some embodiments of the invention provide immunoconjugates wherein the antibody is a monoclonal antibody.
  • the monoclonal antibody is a humanized monoclonal antibody.
  • the antibody construct or antigen binding domain binds to HER2 on a cancer or immune cell at a higher affinity than a corresponding HER2 antigen on a non-cancer cell.
  • the antibody construct or antigen binding domain may preferentially recognize HER2 containing a polymorphism that is found on a cancer or immune cell as compared to recognition of a corresponding wild-type HER2 antigen on the non-cancer cell.
  • the antibody construct or antigen binding domain binds a cancer cell with greater avidity than a non-cancer cell.
  • the cancer cell can express a higher density of HER2, thereby providing for a higher affinity binding of a multivalent antibody to the cancer cell.
  • the antibody construct or antigen binding domain does not significantly bind non-cancer antigens (e.g., the antibody binds one or more non-cancer antigens with at least 10, 100, 1,000, 10,000, 100,000, or 1,000,000-fold lower affinity (higher Kd) than HER2).
  • the corresponding non-cancer cell is a cell of the same tissue or origin that is not hyperproliferative or otherwise cancerous.
  • HER2 need not be specific to the cancer cell or even enriched in cancer cells relative to other cells (e.g., HER2 can be expressed by other cells).
  • the term “specifically” refers to the specificity of the antibody construct and not to the uniqueness of the presence of HER2 in that particular cell type.
  • HER2 expression refers to a cell that has a HER2 receptor on the cell’s surface.
  • a cell may have from about 20,000 to about 50,000 HER2 receptors on the cell’s surface.
  • HER2 overexpression refers to a cell that has more than about 50,000 HER2 receptors (IHC1+). For example, a cell with 2, 5, 10, 100, 1,000, 10,000, 100,000, or 1,000,000 times the number of HER2 receptors as compared to corresponding non-cancer cell (e.g., about 1 or 2 million HER2 receptors).
  • HER2 is overexpressed (i.e., HER2 IHC3+) in about 15% to about 20% of breast cancers.
  • the cells’ expression level of HER2 can be determined by any suitable gene expression technique (e.g., RNA).
  • HER2-amplified cancer refers to a cell that amplifies the production of the HER2 gene.
  • the amplification of HER2 can be determined by any suitable technique, e.g., by sequencing or in situ hybridization (ISH).
  • ISH in situ hybridization
  • NGS next generation sequencing
  • NGS platforms report copy-number variations per their respective algorithm.
  • the cancer cell treated by the method of the invention can be amplified or not amplified.
  • the cancer cell can be characterized by immunohistochemical (IHC) staining.
  • the cancer cell treated by the method of the invention can be IHCO, IHC1+, IHC2+, or IHC3+. If the IHC result is 0 or 1+, the cancer is considered HER2 -negative or low, unless the cancer is Zffi7?2-gene amplified. If the IHC result is 3+, the cancer is considered HER2- positive. If the IHC result is 2+, the HER2 status of the cancer cell is called “equivocal.” This means that the HER2 status needs to be tested with, for example, ISH or sequencing for Zffi7?2-gene amplification to clarify the result.
  • the cancer cell treated by the method of the invention can be any IHC or ISH level, for example, ISH+, ISH-, IHC1+/ISH+, IHC1+/ISH-, IHC2+/ISH+, or IHC2+/ISH-.
  • the antibodies in the immunoconjugates contain a modified Fc region, wherein the modification modulates the binding of the Fc region to one or more Fc receptors.
  • Fc receptor refers to a receptor that binds to the Fc region of an antibody.
  • FcyR which binds to IgG
  • FcaR which binds to IgA
  • FcsR which binds to IgE.
  • the FcyR family includes several members, such as Fcyl (CD64), FcyRIIA (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD 16 A), and FcyRIIIB (CD16B).
  • the Fey receptors differ in their affinity for IgG and also have different affinities for the IgG subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).
  • the antibodies in the immunoconjugates contain one or more modifications (e.g., amino acid insertion, deletion, and/or substitution) in the Fc region that results in modulated binding (e.g., increased binding or decreased binding) to one or more Fc receptors (e.g., FcyRI (CD64), FcyRIIA (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD 16a), and/or FcyRIIIB (CD16b)) as compared to the native antibody lacking the mutation in the Fc region.
  • FcyRI CD64
  • FcyRIIA CD32A
  • FcyRIIB CD32B
  • FcyRIIIA CD 16a
  • FcyRIIIB CD16b
  • the antibodies in the immunoconjugates contain one or more modifications (e.g., amino acid insertion, deletion, and/or substitution) in the Fc region that reduce the binding of the Fc region of the antibody to FcyRIIB. In some embodiments, the antibodies in the immunoconjugates contain one or more modifications (e.g., amino acid insertion, deletion, and/or substitution) in the Fc region of the antibody that reduce the binding of the antibody to FcyRIIB while maintaining the same binding or having increased binding to FcyRI (CD64), FcyRIIA (CD32A), and/or FcRylllA (CD 16a) as compared to the native antibody lacking the mutation in the Fc region. In some embodiments, the antibodies in the immunoconjugates contain one of more modifications in the Fc region that increase the binding of the Fc region of the antibody to FcyRIIB.
  • modifications e.g., amino acid insertion, deletion, and/or substitution
  • the modulated binding is provided by mutations in the Fc region of the antibody relative to the native Fc region of the antibody.
  • the mutations can be in a CH2 domain, a CH3 domain, or a combination thereof.
  • a “native Fc region” is synonymous with a “wild-type Fc region” and comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature or identical to the amino acid sequence of the Fc region found in the native antibody (e.g., trastuzumab).
  • Native sequence human Fc regions include a native sequence human IgGl Fc region, native sequence human IgG2 Fc region, native sequence human IgG3 Fc region, and native sequence human IgG4 Fc region, as well as naturally occurring variants thereof.
  • Native sequence Fc includes the various allotypes of Fes (see, e.g., Jefferis et al., mAbs, 1(4): 332- 338 (2009)).
  • the mutations in the Fc region that result in modulated binding to one or more Fc receptors can include one or more of the following mutations: SD (S239D), SDIE (S239D/I332E), SE (S267E), SELF (S267E/L328F), SDIE (S239D/I332E), SDIEAL (S239D/I332E/A330L), GA (G236A), ALIE (A330L/I332E), GASDALIE (G236A/S239D/A330L/I332E), V9 (G237D/P238D/P271G/A330R), and VI 1 (G237D/P238D/H268D/P271G/A330R), and/or one or more mutations at the following amino acids: E233, G237, P238, H268, P271, L328 and A330. Additional Fc region modifications for modulating Fc receptor binding are
  • the Fc region of the antibodies of the immunoconjugates are modified to have an altered glycosylation pattern of the Fc region compared to the native non-modified Fc region.
  • Human immunoglobulin is glycosylated at the Asn297 residue in the Cy2 domain of each heavy chain. This TV-linked oligosaccharide is composed of a core heptasaccharide, (N-acetylglucosamine)4(Mannose)3 (GlcNAc4Man3).
  • heptasaccharide Removal of the heptasaccharide with endoglycosidase or PNGase F is known to lead to conformational changes in the antibody Fc region, which can significantly reduce antibody -binding affinity to activating FcyR and lead to decreased effector function.
  • the core heptasaccharide is often decorated with galactose, bisecting GlcNAc, fucose, or sialic acid, which differentially impacts Fc binding to activating and inhibitory FcyR.
  • the modification to alter the glycosylation pattern is a mutation.
  • Asn297 is mutated to glutamine (N297Q).
  • the antibodies of the immunoconjugates are modified to contain an engineered Fab region with a non-naturally occurring glycosylation pattern.
  • hybridomas can be genetically engineered to secrete afucosylated mAb, desialylated mAb or deglycosylated Fc with specific mutations that enable increased FcRyllla binding and effector function.
  • the antibodies of the immunoconjugates are engineered to be afucosylated.
  • the entire Fc region of an antibody construct of the immunoconjugates is exchanged with a different Fc region, so that the Fab region of the antibody is conjugated to a non-native Fc region.
  • the Fab region of trastuzumab which normally comprises an IgGl Fc region
  • the Fab region of nivolumab which normally comprises an IgG4 Fc region
  • IgGl IgG2, IgG3, IgAl, or IgG2.
  • the Fc modified antibody with a non-native Fc domain also comprises one or more amino acid modification, such as the S228P mutation within the IgG4 Fc, that modulate the stability of the Fc domain described.
  • the Fc modified antibody with a non-native Fc domain also comprises one or more amino acid modifications described herein that modulate Fc binding to FcR.
  • the modifications that modulate the binding of the Fc region to FcR do not alter the binding of the Fab region of the antibody to its antigen when compared to the native non-modified antibody. In other embodiments, the modifications that modulate the binding of the Fc region to FcR also increase the binding of the Fab region of the antibody to its antigen when compared to the native non-modified antibody.
  • the method includes treating cancer in a subject comprising administering (e.g., administering a therapeutically effective amount of) a compound of formula (I): or a pharmaceutically acceptable salt thereof, i.e., tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof.
  • the method can include treating cancer in a subject comprising administering from about 0.1 mg/kg to about 2,000 mg/kg of tucatinib, or a pharmaceutically acceptable salt thereof, to the subject.
  • the method can include administering tucatinib, or a pharmaceutically acceptable salt thereof, to provide a dose of from about 0.1 mg/kg to about 2,000 mg/kg, from about 0.1 mg/kg to about 1,000 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 0.1 mg/kg to about 400 mg/kg, from about 0.1 mg/kg to about 300 mg/kg, from about 0.1 mg/kg to about 200 mg/kg, from about 0.1 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.1 mg/kg to about 30 mg/kg, from about 0.1 mg/kg to about 20 mg/kg, from about 1 mg/kg to about 2,000 mg/kg, from about 1 mg/kg to about 1,000 mg/kg, from about 1 mg/kg to 500 about mg/kg, from about 1 mg/kg to about 400 mg/kg, from about 1 mg/kg to about 300 mg/kg, from
  • the method includes administering about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, or about 300 mg/kg of tucatinib, or a pharmaceutically acceptable salt thereof, to the subject.
  • tucatinib is administered from about every 1 day to about every 45 days (e.g., about every 1 day, about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 days, about every 9 days, about every 10 days, about every 11 days, about every 12 days, about every 13 days, about every 14 days, about every 15 days, about every 16 days, about every 17 days, about every 18 days, about every 19 days, about every 20 days, about every 21 days, about every 22 days, about every 23 days, about every 24 days, about every 25 days, about every 26 days, about every 27 days, about every 28 days, about every 29 days, about every 30 days, about every 31 days, about every 32 days, about every 33 days, about every 34 days, about every 35 days, about every 36 days, about every 37 days, about every 38 days, about every 39 days, about every 40 days, about every 41 days, about every 42 days, about
  • tucatinib, or a pharmaceutically acceptable salt thereof is administered from about every 3 to about every 35 days. In some embodiments, tucatinib, or a pharmaceutically acceptable salt thereof, is administered every 1, 2, 3, 4, 5, 6, or 7 weeks, or every month. In some embodiments, tucatinib, or a pharmaceutically acceptable salt thereof, is administered from about every 5 to about every 9 days, from about every 6 to about every 8 days, from about every 13 to about every 15 days, from about every 12 to about every 16 days, from about every 20 to about every 22 days, from about every 19 to about every 23 days, from about every 27 to about every 29 days, from about every 26 to about every 30 days, or from about every 33 to about every 37 days.
  • tucatinib, or a pharmaceutically acceptable salt thereof is administered about every 7 days, about every about 14 days, about every 21 days, about every 28 days, about every 35 days, or about every 42 days.
  • Tucatinib, or a pharmaceutically acceptable salt thereof can be administered to the subject as an initial loading dose followed by one or more maintenance doses.
  • tucatinib, or a pharmaceutically acceptable salt thereof can be administered as a loading dose to the subject at about 500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200 mg/kg, about 150 mg/kg, or about 100 mg/kg by IV infusion.
  • the loading dose may be a higher or lower dose than the one or more maintenance doses.
  • the loading dose may be administered to the patient using a similar or different suitable means than the one or more maintenance doses.
  • Tucatinib or a pharmaceutically acceptable salt thereof, can be administered to the subject using any suitable means including parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration (i.e., orally), administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow-release device, e.g., a miniosmotic pump, to the subject.
  • a slow-release device e.g., a miniosmotic pump
  • tucatinib, or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments tucatinib, or a pharmaceutically acceptable salt thereof, is administered (e.g., orally) to the subject at least once weekly. In this regard, tucatinib, or a pharmaceutically acceptable salt thereof, can be administered twice weekly, three times weekly, 4 times weekly, 5 times weekly, 6 times weekly, at least once daily, at least twice daily, or at least three times daily. In some embodiments, tucatinib, or a pharmaceutically acceptable salt thereof, is administered (e.g., orally) once daily. In certain embodiments, tucatinib, or a pharmaceutically acceptable salt thereof, is administered (e.g., orally) twice daily.
  • Tucatinib, or a pharmaceutically acceptable salt thereof can be administered to the subject for any suitable length of time.
  • tucatinib, or a pharmaceutically acceptable salt thereof can be administered to the subject once daily or twice daily for any suitable amount of time.
  • tucatinib or a pharmaceutically acceptable salt thereof, can be administered for a duration of from about 1 month to about 48 months (e.g., from about 1 to about 45 months, from about 1 to about 40 months, from about 1 to about 35 months, from about 1 to about 30 months, from about 1 to about 25 months, from about 1 to about 20 months, from about 1 to about 15 months, from about 1 to about 12 months, from about 1 to about 10 months, from about 1 to about 5 months, from about 1 to about 4 months, from about 1 to about 3 months, from about 1 to about 2 months, or about 1 month).
  • Immunoconjugate Composition e.g., from about 1 to about 45 months, from about 1 to about 40 months, from about 1 to about 35 months, from about 1 to about 30 months, from about 1 to about 25 months, from about 1 to about 20 months, from about 1 to about 15 months, from about 1 to about 12 months, from about 1 to about 10 months, from about 1 to about 5 months, from about 1 to about 4 months, from about 1 to
  • the immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, and tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof are administered simultaneously (i.e., as a single composition).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be for use as a medicament for treating cancer in a subject having cancer in accordance with any embodiment described herein.
  • the immunoconjugate in the composition comprises a plurality of immunoconjugates as defined herein, which immunoconjugates can be the same (i.e., a homogeneous mixture) or different (i.e., a heterogeneous mixture).
  • the composition can comprise immunoconjugates that have the same number of therapeutic agents conjugated to the same positions on the antibody construct and/or immunoconjugates that have the same number of therapeutic agents conjugated to different positions on the antibody construct, that have different numbers of therapeutic agents conjugated to the same positions on the antibody construct, or that have different numbers of therapeutic agents conjugated to different positions on the antibody construct.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the combination of the immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, and tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof can be formulated for parenteral administration, such as IV administration or administration into a body cavity or lumen of an organ.
  • the combination of the immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, and tucatinib (commercially available as TUCYSATM), or a pharmaceutically acceptable salt thereof can be injected intra-tum orally.
  • Compositions for injection will commonly comprise a solution of the immunoconjugate dissolved in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer’s solution.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed, including synthetic monoglycerides or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables.
  • These compositions desirably are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well known sterilization techniques.
  • compositions can contain pharmaceutically acceptable auxiliary substances (e.g., pharmaceutically acceptable excipients) as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • pharmaceutically acceptable auxiliary substances e.g., pharmaceutically acceptable excipients
  • pH adjusting and buffering agents e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • the composition can contain any suitable concentration of the immunoconjugate.
  • concentration of the immunoconjugate in the composition can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the subject’s needs.
  • concentration of an immunoconjugate in a solution formulation for injection will range from about 0.1% (w/w) to about 10% (w/w).
  • the composition can contain any suitable concentration of tucatinib.
  • concentration of tucatinib in the composition can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the subject’s needs.
  • concentration of tucatinib in a solution formulation for injection will range from about 0.1% (w/w) to about 10% (w/w).
  • the composition further comprises an additional therapy (e.g., an additional therapeutic) described herein.
  • the composition may further comprise an agent selected from a chemotherapeutic, a hormone, an immunotherapeutic, a monoclonal antibody, an antibody-drug conjugate, a tyrosine kinase inhibitor, and a combination thereof.
  • the invention provides a method for treating cancer.
  • the method includes administering (e.g., administering a therapeutically effective amount of) (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, and (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, to a subject, e.g., a subject that has cancer and is in need of treatment for the cancer.
  • a subject e.g., a subject that has cancer and is in need of treatment for the cancer.
  • trastuzumab and pertuzumab, biosimilars thereof, and biobetters thereof are known to be useful in the treatment of cancer, particularly breast cancer, especially HER2- overexpressing breast cancer, gastric cancer, especially HER2-overexpressing gastric cancer, and gastroesophageal junction adenocarcinoma.
  • the combination therapy can be used to treat the same types of cancers as trastuzumab, pertuzumab, biosimilars thereof, and biobetters thereof, particularly breast cancer, especially HER2-overexpressing breast cancer, gastric cancer, especially HER2-overexpressing gastric cancer, gastroesophageal junction adenocarcinoma, head and neck cancer, bladder cancer, urothelial (e.g., uterine) cancer, ovarian cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, salivary gland cancer, colorectal cancer, endometrial cancer, liver cancer, or lung cancer.
  • breast cancer especially HER2-overexpressing breast cancer
  • gastric cancer especially HER2-overexpressing gastric cancer, gastroesophageal junction adenocarcinoma, head and neck cancer
  • bladder cancer urothelial (e.g., uterine) cancer, ovarian cancer, gall bladder cancer, bile duct cancer, cervical cancer, e
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is breast cancer.
  • Breast cancer can originate from different areas in the breast, and a number of different types of breast cancer have been characterized.
  • combination therapy of the invention can be used for treating ductal carcinoma in situ; invasive ductal carcinoma (e.g., tubular carcinoma; medullary carcinoma; mucinous carcinoma; papillary carcinoma; or cribriform carcinoma of the breast); lobular carcinoma in situ; invasive lobular carcinoma; inflammatory breast cancer; and other forms of breast cancer.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is gastric cancer.
  • Gastric (stomach) cancer can originate from different cells in the stomach and several types of gastric cancer have been characterized including adenocarcinoma, carcinoid tumors, squamous cell carcinoma, small cell carcinoma, leiomyosarcoma, and gastrointestinal stromal tumors.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is gastroesophageal junction carcinoma.
  • This carcinoma occurs in the area where the esophagus meats the stomach.
  • Type 1 the cancer the cancer grows down from above and into the gastroesophageal junction. The normal lining of the lower end of the esophagus is replaced by mutations (also called Barrett’s esophagus).
  • Type 2 the cancer grows at the gastroesophageal junction by itself.
  • Type 3 the cancer grows up into the gastroesophageal junction from the stomach upwards.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is colorectal. This carcinoma occurs in the colon and/or rectum.
  • the most common type of colorectal cancer is adenocarcinoma.
  • Other types of colorectal cancer include adenosquamous and squamous cell carcinoma.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is lung cancer.
  • Lung cancer begins in the lungs.
  • Types of lung cancer include small cell lung cancer and non-small cell lung cancers.
  • Non-small cell lung cancers include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.
  • Some embodiments of the invention provide method for treating cancer as described above, wherein the cancer has metastasized.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is endometrial.
  • This carcinoma occurs in the layer of cells that form the lining (endometrium) of the uterus.
  • Types of endometrial cancer include edenocarcinoma, uterine carcinosarcoma, squamous cell carcinoma, small cell carcinoma, transitional carcinoma, and serous carcinoma.
  • Some embodiments of the invention provide a method for treating cancer as described above, wherein the cancer is salivary gland.
  • This carcinoma occurs in salivary gland.
  • Types of salivary gland cancer include acinic cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, clear cell carcinoma, malignant mixed tumor, mucoepidermoid carcinoma, oncocytic carcinoma, polymorphous low-grade adenocarcinoma, salivary duct carcinoma, and squamous cell carcinoma.
  • Some embodiments of the invention provide a method for treating cancer in a subject.
  • the subject is a human.
  • a pharmaceutical composition comprising: (i) an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof, wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier.
  • an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, (ii) a compound of formula (I): or
  • SEQ ID NO: 2 as light chain complementary determining region- 1 (CDRL1);
  • SEQ ID NO: 3 as light chain complementary determining region-2 (CDRL2)
  • SEQ ID NO: 4 as light chain complementary determining region-3 (CDRL3), and a second variable region comprising:
  • SEQ ID NO: 5 as heavy chain complementary determining region-1 (CDRH1);
  • SEQ ID NO: 6 as heavy chain complementary determining region-2 (CDRH2); and SEQ ID NO: 7 as heavy chain complementary determining region-3 (CDRH3).
  • an agent selected from a chemotherapeutic, a hormone, an immunotherapeutic, a monoclonal antibody, an antibody-drug conjugate, a tyrosine kinase inhibitor, and a combination thereof.
  • a method for treating cancer in a subject comprising administering (e.g., administering a therapeutically effective amount of):
  • an immunoconjugate of formula: Ab-[TA] r or a pharmaceutically acceptable salt thereof wherein “Ab” is an antibody construct that has an antigen binding domain that binds human epidermal growth factor receptor type 2 (HER2), and “TA” is a therapeutic agent of formula: wherein n is from about 2 to about 25 and r is an average therapeutic agent to antibody ratio from about 1 to about 10, and (ii) a compound of formula (I): or a pharmaceutically acceptable salt thereof, to a subject having cancer.
  • SEQ ID NO: 2 as light chain complementary determining region- 1 (CDRL1);
  • SEQ ID NO: 3 as light chain complementary determining region-2 (CDRL2); and SEQ ID NO: 4 as light chain complementary determining region-3 (CDRL3), and a second variable region comprising: SEQ ID NO: 5 as heavy chain complementary determining region-1 (CDRH1);
  • SEQ ID NO: 6 as heavy chain complementary determining region-2 (CDRH2)
  • SEQ ID NO: 7 as heavy chain complementary determining region-3 (CDRH3).
  • 100 mg/kg of the immunoconjugate or a pharmaceutically acceptable salt thereof is administered to the subject having cancer.
  • BDC-1001.S A BDC-1001 surrogate (BDC-1001.S) was developed that could activate murine myeloid APCs.
  • BDC-1001.S has a slightly reduced TNFa ECso of 281 nM in murine splenocytes.
  • BDC-1001. S is a trastuzumab biosimilar (commercially available from EirGenix, Inc.) covalently attached to a murine TLR7 agonist (i.e., l-(4-aminobutyl)-2-butyl- 17/-imidazo[4,5-c]quinolin-4-amine) via a non-cleavable (PEG6) linker.
  • a murine TLR7 agonist i.e., l-(4-aminobutyl)-2-butyl- 17/-imidazo[4,5-c]quinolin-4-amine
  • % TGI for the NCI-H2170 cell line the % TGI for the JIMT-1 cell line, and the % TGI for the HCC1954 cell line are set forth in Table 1, and plotted in FIGs. 2B-2D, respectively. Table 1. Tumor Growth Inhibition Percentage (% TGI)
  • tumors i.e., NCI-H2170, HCC1954, or JIMT-1
  • BDC-1001.S or trastuzumab was dosed at 2 mg/kg q5d x 4 i.p. (i.e., intraperitoneal administration) in mice bearing NCI-H2170 and HCC1954 tumors and at 5 mg/kg q5d x 4 i.p. (i.e., intraperitoneal administration) in mice bearing JIMT-1 tumors.
  • Tucatinib was dosed at 100 (HCC1954), 150 (NCI-H2170), or 200 (JIMT-1) mg/kg qd x 15 p.o. (i.e., oral administration).
  • Percent tumor growth inhibition was calculated relative to isotype control (rituximab). P-values were calculated by one-way ANOVA with Tukey multiple comparisons corrections, where pval ⁇ 0.05.
  • BDC-1001.S is a suitable surrogate for BDC- 1001, as determined by its ability to elicit myeloid activation in cellular assays.
  • BDC-1001 elicits enhanced myeloid activation as defined by increased expression of TNFa relative to trastuzumab or the mixture of trastuzumab and the molar equivalent of a conjugate that corresponds to BDC-1001 without trastuzumab (Al 03).
  • P-values were calculated by oneway ANOVA with Tukey multiple comparisons corrections, where p ⁇ 0.0001 (****) and p ⁇ 0.01 (**).

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Abstract

L'invention concerne une méthode de traitement du cancer chez un sujet par l'administration (I) d'un immunoconjugué de formule Ab-[TA]r ou d'un sel pharmaceutiquement acceptable de celui-ci, "Ab" étant une construction d'anticorps qui a un domaine de liaison à l'antigène qui se lie au récepteur de facteur de croissance épidermique humain de type 2 (HER2), et "TA" étant un agent thérapeutique de formule, n étant compris entre environ 2 et environ 25 et r étant un rapport entre un agent thérapeutique moyen et anticorps compris entre environ 1 et environ 10, et (ii) un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, à un sujet atteint d'un cancer.<sb />
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