WO2023246911A1 - Molécule polypeptidique bispécifique à base de récepteur de lymphocytes t et son utilisation - Google Patents
Molécule polypeptidique bispécifique à base de récepteur de lymphocytes t et son utilisation Download PDFInfo
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- WO2023246911A1 WO2023246911A1 PCT/CN2023/101881 CN2023101881W WO2023246911A1 WO 2023246911 A1 WO2023246911 A1 WO 2023246911A1 CN 2023101881 W CN2023101881 W CN 2023101881W WO 2023246911 A1 WO2023246911 A1 WO 2023246911A1
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K—PEPTIDES
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
Definitions
- the present invention relates to T cell receptor-based bispecific polypeptide molecules and their uses, particularly in the treatment of cancer, infectious diseases, autoimmune diseases and/or inflammatory diseases.
- T cells are an important component of the adaptive immune system of vertebrates and play a crucial role in viral infection, cancer, and autoimmunity.
- TCR recognition of major histocompatibility complex (MHC)-antigen peptide complex (pMHC) is an important step in T cell-mediated immune response.
- MHC major histocompatibility complex
- pMHC antigen peptide complex
- the non-covalent binding of TCR to the CD3 signaling apparatus consisting of ⁇ , ⁇ , ⁇ and ⁇ subunits forms the TCR–CD3 complex. Binding of pMHC to the TCR activates LCK-induced phosphorylation of the intracellular immunoreceptor tyrosine-based activation motif (ITAM) in the CD3 ⁇ subunit of the TCR.
- ITAM immunoreceptor tyrosine-based activation motif
- CD3 ⁇ phosphorylation then triggers a cascade of phosphorylation signaling involving ⁇ chain-associated protein kinase 70 (ZAP70) and the activated T cell adapter (LAT) in T cells, causing the recruitment of multiple downstream adapters and signaling molecules as well as LAT Formation of the signal body.
- the assembled LAT signalosome activates a variety of signaling pathways involving transcription factors, such as activating protein 1 (AP-1), nuclear factor- ⁇ B (NF- ⁇ B), and nuclear factor of activated T cells (NFAT).
- AP-1 activating protein 1
- NF- ⁇ B nuclear factor- ⁇ B
- NFAT nuclear factor of activated T cells
- Activated transcription factors can cause subsequent T cell activation, proliferation, cytokine production, and effector functions.
- Bispecific antibody refers to an antibody molecule that targets two antigens at the same time or targets two different epitopes of one antigen. Compared with ordinary antibodies, bispecific antibodies have stronger specificity, can more accurately target tumor cells, and reduce off-target toxicity. With the development of recombinant protein expression technology and antibody engineering technology, many different antibody forms have been produced. Multispecific antibodies are used for a variety of purposes, including (1) receptor activation (2) blocking (3) internalization (4) aggregation, (5) binding of membrane-associated proteins, or (6) cytotoxic effector cells Orientation target.
- T cell repositioning bsAb (also known as T cell engager, TcE) is an important form of cytotoxic effector cell repositioning and is the central pillar of current cancer immunotherapy.
- This bsAb recognizes the target on the surface of tumor cells and also recognizes a molecule on the surface of T cells (the molecule is CD3 in most cases), so that the bsAb can couple tumor cells and cytotoxic T cells together to Causes the activation of T cell TCR downstream signaling pathways and kills tumor cells through T cell cytotoxicity.
- Blincyto (blinatumomab) is a CD19/CD3 bispecific antibody that leads to complete remission in 69% of patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).
- ALL relapsed/refractory B-precursor acute lymphoblastic leukemia
- a large number of new T cell relocalizing antibody forms have emerged, such as BITE, BITE-Fc, DART-Fc, TriTAC, etc.
- TCR can recognize the antigen peptides of intracellular and cell surface tumor-specific antigens that are processed and presented on the cell surface MHC molecules, and the recognition range is wider.
- the target cell recognition region in TCR-based T cell repositioning bispecific antibodies is changed from traditional antibodies to TCR, so that the broad recognition properties of TCR can be used to increase target selectivity.
- the potency of TcE against TCR of target cell targets can also be increased, and the potency of TcE against surface molecules on effector cells can also be increased to enhance T cell killing activity and proliferation ability.
- the molecular size of TcE needs to be maintained within a certain range.
- the glomerular filtration limit is generally around 60kDa.
- Nanobodies 15kDa
- scFv 28kDa
- Fab 50kDa
- Nanobodies have the smallest molecular weight among all antibody types, and their half-lives are often only tens of minutes. Therefore, in order to increase the efficacy of protein drugs, it is necessary to improve protein drugs to extend their half-life and increase activity.
- Appropriately adding other functional domains to the polypeptide molecule can not only extend the length of the polypeptide molecule
- the half-life can also enhance the killing activity of polypeptide molecules.
- the present invention provides TCR-based bispecific polypeptide molecules.
- the bispecific polypeptide molecule of the present invention adopts a specific antigen-binding region connection method and is combined with the TCR constant region (TRAC and TRBC). This combination with the TCR constant region significantly improves the stability of the molecule. This combination of each structural domain The specific combination achieved highly efficient immune cell activation and was significantly more effective than using the constant region of the antibody (CH3, hinge region-CH2-CH3, or CH1/CL).
- the term “comprises” and variations thereof such as “includes” and “contains” shall be understood to mean the inclusion of stated elements or steps but not the exclusion of any other elements or steps.
- the term “consisting of” is considered to be a preferred embodiment of the term “comprising”. If a group is defined below as including or containing at least a certain number of embodiments, this is also to be understood as disclosing a group that preferably consists exclusively of these embodiments.
- T cell receptor or "TCR” as used herein includes native TCR as well as TCR variants, fragments and constructs. The term therefore includes heterodimers as well as multimeric and single-chain constructs comprising TCR alpha and TCR beta chains; optionally including other domains and/or portions, so long as the TCR retains its ability to recognize the antigenic target.
- TCR In its native form, the TCR exists as a complex of several proteins on the surface of T cells.
- T cell receptors are composed of two (separate) protein chains produced by separate T cell receptor alpha and beta (TCR ⁇ and TCR ⁇ ) genes and are called alpha and beta chains.
- Each chain of the TCR has an N-terminal immunoglobulin-like (Ig)-variable (V) region/domain and an Ig-constant (C) region/domain that anchors the chain across the membrane in the plasma membrane. /membrane spanning region, and a short cytoplasmic tail at the C-terminus.
- Ig immunoglobulin-like
- V immunoglobulin-like
- C Ig-constant
- variable regions of the alpha and beta chains (TRAV and TRBV). Both variable regions of the TCR ⁇ chain and ⁇ chain contain three hypervariable or complementarity determining regions (CDR1 ⁇ / ⁇ , CDR2 ⁇ / ⁇ and CDR3 ⁇ / ⁇ ) surrounded by framework (FR) regions.
- CDR3 is the major determinant of antigen recognition and specificity (i.e., the ability to recognize and interact with a specific antigen), while CDR1 and CDR2 interact primarily with MHC molecules presenting antigenic peptides.
- the TCR recognizes an antigenic peptide that binds to a major histocompatibility complex (MHC) molecule at the surface of the antigen-presenting cell ("presented/displayed on the MHC molecule").
- MHC major histocompatibility complex
- Antigenic peptides presented on MHC molecules are also referred to herein as “antigenic peptides” "Epitope-MHC complex”, “epitope-MHC complex”, "antigen-MHC complex” or "target antigen peptide-MHC complex”.
- MHC I and MHC II which presents peptides from different cellular compartments.
- MHC class I molecules are expressed on the surface of all nucleated cells in the human body and display peptides or protein fragments from intracellular compartments to cytotoxic T cells. In humans, MHC is also called human leukocyte antigen (HLA). There are three main types of MHC class I: HLA-A, HLA-B, and HLA-C. Once the TCR binds to its specific epitope-MHC complex, the T cell is activated and functions Biological effect function.
- TCR constant region includes the TCR alpha chain constant region (TRAC) and the beta chain constant region (TRBC), which may be human constant regions or derived from another species, such as murine.
- the sequence of the wild-type TCR constant region can be found in the public database of the International Immunogenetic Information System (IMGT).
- IMGT International Immunogenetic Information System
- the constant domain sequence of the ⁇ chain of the TCR molecule is "TRAC*01”
- the constant domain sequence of the ⁇ chain of the TCR molecule is " TRBC1*01” or "TRBC2*01”.
- the positions of the amino acid sequences of the wild-type TCR in the present invention are numbered according to the naming rules of the International Immunogenetic Information System (IMGT). For example, if a certain amino acid in the TCR ⁇ chain variable region (TRAV) has a position number of 104 listed in IMGT, it is described in the present invention as the 104th amino acid of TRAV; in the TCR ⁇ chain variable region (TRBV) For a certain amino acid, if the position number listed in IMGT is 84, it will be described as the 84th amino acid of TRBV in the present invention; for others, the same applies.
- IMGT International Immunogenetic Information System
- an amino acid in the constant region of TCR ⁇ chain is 48, then it is described in this article as the 48th amino acid of TRAC;
- an amino acid in the constant region of TCR ⁇ chain (TRBC) is 57, then it is described in this article as the 57th amino acid of TRBC; others are deduced by analogy.
- TRBC constant region of TCR ⁇ chain
- the special instructions will apply.
- antibody refers to an immunoglobulin molecule that has the ability to specifically bind to a specific antigen.
- Such molecules typically contain two heavy (H) chains and two light (L) chains interconnected by disulfide bonds.
- Each heavy chain consists of a heavy chain variable region (or domain) (herein abbreviated as VH) and a heavy chain constant region.
- the heavy chain constant region consists of three domains, CH1, CH2 and CH3.
- Each light chain consists of a light chain variable region (or domain) (herein abbreviated as VL) and a light chain constant region.
- the light chain constant region consists of one domain, CL.
- the variable regions of the antibody heavy and light chains contain binding domains that interact with the antigen.
- the constant region of an antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system such as C1q (the third step in the classical pathway of complement activation). one component).
- the heavy chain of immunoglobulins can be divided into three functional regions: Fd region, hinge region and Fc region (crystallizable fragment).
- the Fd region contains VH and CH1 domains and combines with the light chain to form Fab (antigen-binding fragment).
- the Fc region also called an Fc domain, contains two or three heavy chain constant regions (CH2, CH3, CH4) in each heavy chain. In IgG class antibodies, the Fc region contains CH2 and CH3 domains.
- the Fc regions of the two heavy chains dimerize to form the dimerization part.
- the Fc fragment is responsible for immunoglobulin effector functions, including, for example, complement fixation and binding to cognate Fc receptors on effector cells.
- the hinge region of IgG antibodies refers to the short amino acid sequence region between the CH1 and CH2 parts of the heavy chain, which is relatively flexible in the natural state of the antibody.
- the hinge region found in the IgG, IgA and IgD immunoglobulin classes acts as a flexible spacer, allowing the Fab portion to move freely in space relative to the Fc region.
- Hinge domains are structurally diverse, varying in sequence and length between immunoglobulin classes and subclasses. Based on crystallographic studies, the immunoglobulin hinge region can be further subdivided into three regions structurally and functionally: upper hinge, core hinge, and lower hinge (Shin et al., Immunological Reviews 130:87, 1992).
- the upper hinge includes from the carboxyl terminus of CH1 to the first residue in the hinge that limits movement.
- Amino acid usually the first cysteine residue that forms an interchain disulfide bond between two heavy chains.
- the length of the upper hinge region correlates with the fragment flexibility of the antibody.
- the core hinge region contains inter-heavy chain disulfide bonds.
- the lower hinge region connects the amino terminus of the CH2 domain and includes residues in the CH2 domain.
- the core hinge region of human IgG1 contains the sequence Cys-Pro-Pro-Cys (SEQ ID NO:7) which when dimerized through disulfide bonds results in a cyclic octapeptide, which is believed to act as a pivot, Thus imparting flexibility.
- the structure and flexibility of the immunoglobulin hinge region polypeptide sequence allow for conformational changes that can affect the effector function of the Fc portion of the antibody.
- a “light chain variable region (VL)” or “heavy chain variable region (VH)” consists of a “framework” region interspersed with three “complementarity determining regions” or “CDRs".
- the framework region is used to adjust the CDR for specific binding to the antigenic epitope.
- the CDRs contain the amino acid residues in the antibody that are primarily responsible for antigen binding. From the amino terminus to the carboxyl terminus, both VL and VH domains contain the following framework (FR) regions and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- Kabat provides a widely used numbering convention (Kabat numbering system) in which corresponding residues between different heavy chains or between different light chains are assigned the same number.
- the present disclosure may use CDRs defined according to any of these numbering systems, but the preferred embodiment uses CDRs defined by Kabat.
- antibody is to be understood in its broadest sense and includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, antibody fragments and multispecific antibodies containing at least two antigen-binding regions (e.g., bispecific antibodies). Antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations at glycosylation sites. Antibodies also include post-translationally modified antibodies, fusion proteins containing the antigenic determinants of the antibodies, and immunoglobulin molecules containing any other modifications to the antigen recognition site, so long as these antibodies exhibit the intended biological activity.
- antigen-binding fragment of an antibody refers to one or more antibody fragments that retain the ability to specifically bind an antigen. It has been shown that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.
- antigen-binding fragments include, but are not limited to (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments, including Two Fab fragments connected by a disulfide bond in the hinge region; (iii) Fab' fragment, which is essentially a Fab but has a partial hinge region (see, FUNDAMENTAL IMMUNOLOGY (Paul ed., 3.sup.rd ed.
- the two domains of the Fv fragment, VL and VH are encoded by independent genes, They can be linked using recombinant methods via synthetic linkers that enable them to form a single protein chain in which the VL and VH regions pair to form a monovalent molecule (termed a single-chain Fv (ScFv); see e.g. Bird et al. Human (1988) Science 242, 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85, 5879-5883).
- Such single chain antibodies are also intended to be included in the term "antigen-binding fragment" of an antibody Within.
- the term also includes "linear antibodies” containing a pair of tandem Fd fragments (VH-CH1-VH-CH1) formed with a complementary light chain polypeptide and modified versions of any of the foregoing fragments that retain antigen-binding activity Antigen binding region.
- antigen refers to any substance capable of inducing an immune response in the body. That is, it can be specifically recognized and combined with the antigen receptor (TCR/BCR) on the surface of T/B lymphocytes, activate T/B cells, cause them to proliferate and differentiate, produce immune response products (sensitized lymphocytes or antibodies), and can Substances that specifically bind to corresponding products in vivo and in vitro.
- TCR/BCR antigen receptor
- the antigen may be a tumor-associated antigen (TAA), a tumor-specific antigen (TSA), a viral antigen, an autoantigen, and an immune cell surface molecule.
- TAA tumor-associated antigen
- TSA tumor-specific antigen
- viral antigen an autoantigen
- autoantigen an immune cell surface molecule
- tumor-associated antigen refers to an antigen that is differentially expressed (eg, significantly increased in expression on tumor cells) compared to normal cells.
- TSA tumor-specific antigen
- viral antigen refers to a substance in a virus that can induce an immune response in the body.
- autoantigen refers to antigenic substances that cause changes in the structure and components of self-tissue cells caused by biological, physical, and chemical factors, thereby causing the body's immune system to produce an immune response against these self-tissue cell components.
- the release of cryptic antigens generates an immune response.
- Changes in its own composition may produce autoantigens.
- denatured IgG can stimulate the body to produce anti-denatured IgG antibodies (rheumatoid factor), causing rheumatoid arthritis.
- the clinical use of certain drugs can change the antigenicity of blood cell surface, causing autoimmune hemolytic anemia or neutropenia. Cross-reactions triggered by common antigens can generate immune responses.
- Certain bacteria and viruses have similar antigenic determinants to certain tissue cells of the normal human body. Autoantibodies and sensitized lymphocytes produced against the antigenic determinants of these bacteria and viruses can cross-react with their own tissue cells, causing autoimmunity. disease.
- Immuno cell surface molecules may include, for example, immune cell surface antigens (eg, T cell antigens) and costimulatory molecules.
- Epitopes can be formed from contiguous amino acids or non-contiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed by consecutive amino acids (also called linear epitopes) are usually retained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding (also called conformational epitopes) are usually lost upon treatment with denaturing solvents. Epitopes typically comprise at least 3, more typically at least 5 or 8-10 amino acids in a unique spatial conformation. The epitope defines the minimal binding site of the TCR or antibody and is therefore the specific target of the TCR or antibody or its antigen-binding fragment.
- albumin encompasses any naturally occurring albumin from any vertebrate source, including mammals, such as primates (e.g., humans and monkeys) and rodents (e.g., mice and rats). mouse). Albumin also encompasses the full-length, unprocessed preproalbumin protein as well as any form of albumin resulting from processing in the cell. Albumin also encompasses variants of naturally occurring albumin, such as splice variants or allelic variants. The term also covers any recombinant form of albumin. Albumin sequences are known in the art. Information on the human serum albumin gene (including genomic DNA sequence) can be found, for example, at NCBI.
- the amino acid sequence of an exemplary full-length human serum albumin preproprotein can be found under NCBI accession number NP_000468.1.
- Human serum albumin is synthesized in the form of prealbumin.
- Mature albumin is a single-chain polypeptide of 585 amino acid residues with a molecular weight of 66,458. The molecule contains 17 disulfide bonds and does not contain sugar components.
- albumin is a negative ion, and each molecule can carry more than 200 negative charges.
- About 10% of exogenously infused albumin enters the extravascular tissue space after 2 hours, and reaches equilibrium in 20 days. The half-life of albumin in plasma is 15-19 days.
- sequence identity refers to the extent to which two sequences (amino acids) aligned have identical residues at the same positions.
- amino acid sequence is X% identical to SEQ ID NO:Y
- sequence residues in the amino acid sequence are identical to SEQ ID NO :
- sequence residues disclosed in Y are identical.
- Exemplary programs for comparing and aligning sequence pairs include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al. People, 1984).
- Such conservative amino acid substitutions are well known in the art, for example WO 04/037999, GB-A-2 357 768, WO 98/49185, WO 00/46383 and WO 01/09300; and (preferably) these substitutions
- the type and/or combination may be selected based on the relevant teachings from WO 04/037999 and WO 98/49185 and further references cited therein.
- Such conservative substitutions are preferably substitutions in which one amino acid of the following groups (a) to (e) is replaced by another amino acid residue of the same group: (a) small aliphatic, non-polar or weakly polar Residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, non-polar residues: Met, Leu, He, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp.
- Particularly preferred conservative substitutions are as follows: Ala to Gly or to Ser; Arg to Lys; Asn to Gln or to His; Asp to Glu; Cys to Ser; Gln to Asn; Glu to Asp; Gly to Ala or to Pro; His To Asn or to Gln; Ile to Leu or to Val; Leu to Ile or to Val; Lys to Arg, to Gln or to Glu; Met to Leu, to Tyr or to Ile; Phe to Met, to Leu or to Tyr; Ser to Thr; Thr to Ser; Trp to Tyr; Tyr to Trp; and/or Phe to Val, to Ile or to Leu.
- vector is a nucleic acid molecule used as a vehicle for the transfer of (exogenous) genetic material into a host cell in which said nucleic acid molecule as a vector can, for example, be replicated and/or expressed.
- host cell refers to any type of cell into which an expression vector has been introduced thereby capable of expressing foreign genetic material.
- pharmaceutically acceptable means that the carrier or adjuvant is compatible with the other ingredients of the composition and is not substantially toxic to the recipient thereof, and/or that such carrier or adjuvant is approved or available for inclusion in parenteral administration to humans. in pharmaceutical compositions of medicines.
- treatment refers to administering an agent or performing a procedure in order to obtain an effect. These effects may be prophylactic in the sense of completely or partially preventing the disease or its symptoms, and/or may be therapeutic insofar as affecting the partial or complete cure of the disease and/or the symptoms of the disease.
- treating may include treating a disease or condition in a mammal, particularly a human (eg, cancer, infectious disease, autoimmune disease or inflammatory disease), and includes This includes: (a) preventing the occurrence of a disease or symptoms of a disease in subjects who are susceptible to the disease but have not yet been diagnosed with the disease (e.g., including diseases that may be associated with or caused by the primary disease); (b) ) inhibits the disease, i.e. prevents its progression; (c) alleviates the disease, i.e. causes the regression of the disease.
- a mammal particularly a human (eg, cancer, infectious disease, autoimmune disease or inflammatory disease)
- Treatment may refer to any indication of success in treating or ameliorating or preventing cancer, including any objective or subjective parameter, such as elimination; remission; reduction of symptoms or making disease symptoms more tolerable for the patient; slowing of progression or decline ; or reduce the endpoint of worsening frailty. Treatment or improvement of symptoms is based on one or more objective or subjective parameters; including the results of a physician's examination.
- treating includes administering a multispecific polypeptide molecule or pharmaceutical composition or conjugate disclosed herein to prevent or delay, alleviate, or prevent or inhibit the development of symptoms or conditions associated with a disease, such as cancer.
- therapeutic effect refers to the reduction, elimination, or prevention of disease, disease symptoms, or disease side effects in a subject.
- the term "effective amount” as used herein means an amount of a therapeutic agent that when administered to a subject for the treatment or prevention of a disease is sufficient to effect such treatment or prevention.
- the “effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.
- “Therapeutically effective amount” refers to an amount effective for therapeutic treatment.
- a “prophylactically effective amount” refers to an amount effective for prophylactic treatment.
- the term "subject” refers to any mammalian subject for whom diagnosis, treatment, or therapy is desired.
- "Mammal” for therapeutic purposes means any animal classified as a mammal, including humans, domestic animals, and laboratory, zoo, sporting or pet animals, such as dogs, horses, cats, cattle, sheep, Goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc.
- the invention provides a bispecific polypeptide molecule comprising a first binding region that binds a first antigen and a second binding region that binds a second antigen on one or more polypeptide chains. district,
- the first binding region comprises an alpha chain variable region (TRAV) and a beta chain variable region (TRBV) derived from a T cell receptor (TCR) bound to the first antigen-MHC complex;
- TRAV alpha chain variable region
- TRBV beta chain variable region
- the second binding region comprises a heavy chain variable region VH and a light chain variable region VL derived from an antibody that binds to the second antigen;
- the TRAV, TRBV, VH and VL are distributed on the one or more polypeptide chains, so that when the one or more polypeptide chains are folded, the TRAV and TRBV are spatially close to form the first a binding area, and the VH and VL are spatially close to form a second binding area;
- the first antigen is selected from the group consisting of tumor-associated antigens (TAA), tumor-specific antigens (TSA), viral antigens and autoantigens, and the second antigen is an immune cell surface molecule.
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- viral antigens and autoantigens
- the second antigen is an immune cell surface molecule.
- the TRAV, TRBV, VH and VL are distributed on the one or more polypeptide chains and adjacent variable regions on the same chain are separated by linker sequences.
- the bispecific polypeptide molecule comprises a first binding region that binds a first antigen and a second binding region that binds a second antigen on both polypeptide chains,
- the first binding region comprises an alpha chain variable region (TRAV) and a beta chain variable region (TRBV) derived from a T cell receptor (TCR) bound to the first antigen-MHC complex;
- TRAV alpha chain variable region
- TRBV beta chain variable region
- the second binding region comprises a heavy chain variable region VH and a light chain variable region VL derived from an antibody that binds to the second antigen;
- the first antigen is selected from the group consisting of tumor-associated antigens (TAA), tumor-specific antigens (TSA), viral antigens and autoantigens, and the second antigen is an immune cell surface molecule;
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- viral antigens and autoantigens
- the second antigen is an immune cell surface molecule
- the two polypeptide chains of the bispecific polypeptide molecule respectively include:
- the bispecific polypeptide molecule further comprises a TCR constant region or fragment thereof linked to the C-terminus of each polypeptide chain via an optional linker.
- the two polypeptide chains of the bispecific polypeptide molecule comprise: TRAV-VH and VL-TRBV respectively.
- the two polypeptide chains of the bispecific polypeptide molecule respectively comprise: TRAV-VH and VL-TRBV, and adjacent variable regions in the two polypeptide chains are connected by a linker; and
- the bispecific polypeptide molecule further comprises a TCR constant region or fragment thereof linked to the C-terminus of each polypeptide chain via an optional linker.
- the TCR constant region is selected from the group consisting of TCR alpha chain constant region (TRAC) and TCR beta chain constant region (TRBC).
- TRAC TCR alpha chain constant region
- TRBC TCR beta chain constant region
- one polypeptide chain of the bispecific polypeptide molecule comprises TRAC and the other polypeptide chain comprises TRBC.
- 1-5 amino acids at the N-terminus of TRAC may be substituted.
- 1-5 amino acids at the N-terminus of TRBC may be substituted.
- TRAC and TRBC can be of human or murine origin.
- TRAC and TRBC can be wild type or variants thereof.
- the variant TRAC may comprise one or more of T48C, N113K, PESS deletion mutation, FFPSPESS deletion mutation relative to the wild-type sequence.
- the variant TRBC may comprise one or more of S57C, C187A, N210D, and FG loop deletion mutations relative to the wild-type sequence.
- TRAC and/or TRBC comprise at least one cysteine mutation relative to the wild-type sequence to form a disulfide bond between TRAC and TRBC, more preferably, said cysteine mutation At the following positions: position 48 of the wild-type TCR ⁇ chain constant region and position 57 of the wild-type TCR ⁇ chain constant region.
- the polypeptide molecule comprises TRAC or a fragment thereof, which is not cis-linked to TRAV through a linker.
- TRAC or a fragment thereof, which is not cis-linked to TRAV through a linker.
- 1-5 amino acids at the N-terminus of TRAC can be substituted.
- the polypeptide molecule comprises TRBC or a fragment thereof that is not cis-linked to TRBV through a linker.
- TRBC or a fragment thereof that is not cis-linked to TRBV through a linker.
- 1-5 amino acids at the N terminus of TRBC can be substituted.
- cis-linked refers to the connection form of the TCR constant region and the variable region in the natural state.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any The optional linker-TRAC, and the second polypeptide chain from the N-terminus to the C-terminus includes: VL-linker-TRBV-optional linker-TRBC (format 22-2).
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-linker -TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any The optional linker-TRBC, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRBV-optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any The optional linker-TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRBV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any The optional linker-TRBC, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRBV-optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any optional linker-TRAC, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any The optional linker-TRBC, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRAV-optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any The optional linker-TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRAV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any The optional linker-TRBC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRAV-optional linker-TRAC.
- the bispecific polypeptide molecule further comprises at least one of the following functional domains:
- the introduction of the functional domain can not only extend the half-life of the polypeptide molecule, but also enhance the killing activity of the polypeptide molecule.
- the functional domain is linked to the C-terminus of one or both polypeptide chains of the bispecific polypeptide molecule via an optional linker. In some embodiments, the functional domain is linked to the C-terminus of either polypeptide chain of the bispecific polypeptide molecule through an optional linker. In some embodiments, the functional domain is linked to the C-termini of both polypeptide chains of the bispecific polypeptide molecule via an optional linker.
- the functional domain is derived from albumin or a fragment thereof.
- albumin or a fragment thereof is linked to the C-terminus of one or both polypeptide chains of the bispecific polypeptide molecule via an optional linker.
- albumin or a fragment thereof is linked to the C-terminus of either polypeptide chain of the bispecific polypeptide molecule through an optional linker.
- the albumin can be any mammalian source of albumin, such as human albumin, bovine albumin, mouse albumin, etc.
- the albumin is serum albumin, such as human serum albumin or bovine serum albumin.
- the functional domain may be a fragment of albumin, for example, 100-550, 150-550, 200-550, 250-550, 300-550, 350-550, 400-550, 450 in length -550, 500-550, 100-500, 150-500, 200-500, 250-500, 300-500, 350-500, 400-500, 450-500, 100-450, 150-450, 200-450 ,250-450,300-450,350-450,400-450,100-400,150-400,200-400,250-400,300-400,350-400,100-350,150-350,200 -350, 250-350, 300-350, 100-300, 150-300, 200-300, 250-300, 100-250, 150-250, 200-250, 100-200, 150-200, 100-150 fragment of amino acids.
- the albumin is human serum albumin, whose amino acid sequence is shown in SEQ ID NO: 9.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: The first polypeptide chain contains from N-terminus to C-terminus: TRAV-linker-VH-optional linker-TRAC, and the second polypeptide chain contains from N-terminus to C-terminus: VL-linker-TRBV- Optional Linker-TRBC-Optional Linker-Alb (Format64).
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-linker -TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-linker-TRBC-linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any optional linker-TRAC-optional linker-Alb, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRBV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any Optional linker-TRBC-Optional linker-Alb, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-Optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any The optional linker-TRBC, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-optional linker-TRAC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any optional linker-TRAC-optional linker-Alb, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRBV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any The optional linker-TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRBV-optional linker-TRBC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any Optional linker-TRBC-Optional linker-Alb, and the second polypeptide chain includes from N-terminus to C-terminus: VH-Linker-TRBV-Optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any The optional linker-TRBC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRBV-optional linker-TRAC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any optional linker-TRAC-optional linker-Alb, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRAV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any optional linker-TRAC, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRBC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any optional linker-TRBC-optional linker-Alb, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any optional linker-TRBC, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRAC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any optional linker-TRAC-optional linker-Alb, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRAV-optional linker-TRBC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any optional linker-TRAC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRAV-optional linker-TRBC-optional linker-Alb.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any Optional Linker-TRBC-Optional Linker-Alb, and the second polypeptide chain from N-terminus to C-terminus includes: VH-Linker-TRAV-Optional Linker-TRAC.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any The optional linker-TRBC, and the second polypeptide chain includes from N-terminus to C-terminus: VH-linker-TRAV-optional linker-TRAC-optional linker-Alb.
- the functional domain is derived from the hinge region of an antibody and/or the Fc domain of an antibody or a dimerization portion thereof; and the functional domain is linked to the bispecific via an optional linker.
- the hinge region may comprise part or all of the wild-type hinge sequence of the antibody or a variant thereof with one or more substitutions.
- the hinge region of the antibody is that of a human antibody.
- the hinge region of an antibody can be of any isotype, including but not limited to IgG1, IgG2, IgG3, and IgG4.
- the hinge region of an antibody may be derived from the hinge domain of human IgGl, IgG2 or IgG4, or a portion thereof.
- the hinge region may comprise one of the following amino acid sequences: EPKSSDKTHTCPPCPAPPVAGP (SEQ ID NO:69), EPKSSDKTHTCPPCP (SEQ ID NO:70), PKSSDKTHTCPPCPAPPVAGP (SEQ ID NO:71), KSSDKTHTCPPCPAPPVAGP (SEQ ID NO:72) ), SSDKTHTCPPCPAPPVAGP(SEQ ID NO:73), SDKTHTCPPCPAPPVAGP(SEQ ID NO:74), DKTHTCPPCPAPPVAGP(SEQ ID NO:75), KTHTCPPCPAPPVAGP(SEQ ID NO:76), THTCPPCPAPPVAGP(SEQ ID NO:77), HTCPPCPAPPVAGP(SEQ ID NO:78), TCPPCPAPPVAGP(SEQ ID NO:79), CPPCPAPPVAGP(SEQ ID NO:80), PPCPAPPVAGP(SEQ ID NO:81), CPAPPVAGP(SEQ ID NO:82), or PAPPVAGP(SEQ ID NO:69
- the Fc domain of the antibody contains CH2 and CH3.
- the Fc domain of an antibody, or a dimerization portion thereof is that of a human antibody, or a dimerization portion thereof.
- the Fc domain of an antibody can be of any isotype, including but not limited to IgG1, IgG2, IgG3, and IgG4, and can contain one or more mutations or modifications.
- the Fc domain of the antibody, or a dimerization portion thereof is derived from the Fc domain of human IgG1, IgG2, or IgG4, or a portion thereof, and preferably contains at least two cysteine residue mutations, such as S354C and Y349C or L242C and K334C.
- the Fc domain is of the IgG1 isotype or derived therefrom, optionally with one or more mutations or modifications. In another embodiment, the Fc domain is or derived from the IgG4 isotype, optionally with one or more mutations or modifications. In one embodiment, the Fc domain is human IgG1 Fc or human IgG4 Fc.
- the functional domain comprises the hinge region-CH2-CH3 of an antibody.
- both polypeptide chains of the bispecific polypeptide molecule comprise hinge regions -CH2-CH3.
- CH3 in both polypeptide chains of the bispecific polypeptide molecule contains at least one mutation capable of promoting heterodimer formation of the polypeptide molecule.
- the CH3s in both polypeptide chains each independently comprise mutations at one or more positions selected from amino acid positions 366, 368, 405 and 407 and the two CH3s do not comprise the same mutation, preferably , one of the CH3s contains the T366W mutation and the other contains the T366S, L368A and Y407V mutations.
- the amino acid sequence of the hinge region-CH2-CH3 is shown in SEQ ID NO: 33 or 34.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any Optional Connector-TRAC-Optional Connector-Hinge region-CH2-CH3, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-optional linker-TRBC-optional linker-hinge region-CH2-CH3 (format 63) .
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-linker -TRAC-hinge region-CH2-CH3, and the second polypeptide chain includes from N-terminus to C-terminus: VL-linker-TRBV-linker-TRBC-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VH-any Selected linker-TRBC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRBV-optional linker-TRAC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any selected linker-TRAC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRBV-optional linker-TRBC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-linker-VL-any Selected linker-TRBC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRBV-optional linker-TRAC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any selected linker-TRAC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRBC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VH-any selected linker-TRBC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VL-linker-TRAV-optional linker-TRAC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any selected linker-TRAC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRAV-optional linker-TRBC-optional Joint-hinge region-CH2-CH3.
- the bispecific polypeptide molecule comprises a first polypeptide chain and a second polypeptide chain, wherein: the first polypeptide chain comprises from N-terminus to C-terminus: TRBV-linker-VL-any Selected linker-TRBC-optional linker-hinge region-CH2-CH3, and the second polypeptide chain from N-terminus to C-terminus includes: VH-linker-TRAV-optional linker-TRAC-optional Joint-hinge region-CH2-CH3.
- the linkers when the polypeptide molecule comprises more than one linker, the linkers may each be the same or different. In some embodiments, the linkers in the polypeptide molecule are each independently selected from a linker consisting of 1-35 amino acids.
- the linkers are each independently selected from the group consisting of S (SEQ ID NO:41), GGGS (SEQ ID NO:62), GGGGS (SEQ ID NO:42), GGGSGGGG (SEQ ID NO:50), GGSGGS (SEQ ID NO: 47), GGSGGGGGS (SEQ ID NO: 48), GGGSGGGGS (SEQ ID NO: 46), GGGGSGGGGSGGGGS (SEQ ID NO: 44), GGGGSGGGGSGGGGSGGGGSGGGS (SEQ ID NO: 43), GGGGSGGGGSGGGGGGSGGGGS (SEQ ID NO: 43) :45), GQPKAAP (SEQ ID NO:49), TVLRT (SEQ ID NO:53), TVSSAS (SEQ ID NO:54), GGEGG (SEQ ID NO:55), GSEGGGS (SEQ ID NO:56), RTSGPGDGGKGGPGKGPGGEGTKGTGPGG (SEQ ID NO:57), GKGPGGEGTKGTGP
- the variant of EDLKN is the amino acid sequence formed by EDLKN through substitution, deletion or addition of one or several amino acids
- the variant of EDLNK is the amino acid sequence of EDLNK through substitution, deletion or addition of one or several amino acids.
- the formed amino acid sequence; and/or the variant of ANIQK is the amino acid sequence formed by substituting, deleting or adding one or several amino acids of ANIQK.
- the variant of EDLKN is the amino acid sequence formed by substituting one or several amino acids of EDLKN; and/or the variant of EDLNK is the amino acid sequence formed by substituting one or several amino acids of EDLNK; and/or the variation of ANIQK
- the body is the amino acid sequence formed by ANIQK by substituting one or several amino acids.
- the variant of EDLKN is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLNK.
- An amino acid sequence consisting of 1-3 amino acids; and/or a variant of ANIQK is an amino acid sequence consisting of 1-3 amino acids formed by deleting one or several amino acids of ANIQK.
- the variants of EDLKN are EDL, DL, L, ED, E, D; and/or the variants of ANIQK are ANI, NI, I, AN, N, A, PNI, P, PN.
- the variant of EDLKN is an amino acid sequence consisting of 6-35 amino acids formed by adding one or several amino acids to EDLKN (preferably at the N-terminus); and/or the variant of EDLNK is EDLNK after adding (preferably at the N-terminus) N-terminus) an amino acid sequence consisting of 6-35 amino acids formed by one or several amino acids; and/or the variant of ANIQK is ANIQK formed by adding (preferably at the N-terminus) one or several amino acids consisting of 6- An amino acid sequence consisting of 35 amino acids.
- the linkers in the polypeptide molecule are each independently selected from a linker consisting of no more than 12 amino acids.
- the linkers are each independently selected from S, GGGS, GGGGS, GGGSGGGG, GGSGGS, GGSGGSGGS, GGGGSGGGGS, EDLKN or variants thereof, EDLNK or variants thereof and ANIQK or variants thereof.
- the variant of EDLKN is the amino acid sequence formed by EDLKN through substitution, deletion or addition of one or several amino acids; and/or the variant of EDLNK is the amino acid sequence of EDLNK through substitution, deletion or addition of one or several amino acids.
- the formed amino acid sequence; and/or the variant of ANIQK is the amino acid sequence formed by substituting, deleting or adding one or several amino acids of ANIQK.
- the variant of EDLKN is the amino acid sequence formed by substituting one or several amino acids of EDLKN; and/or the variant of EDLNK is the amino acid sequence formed by substituting one or several amino acids of EDLNK; and/or the variation of ANIQK
- the body is the amino acid sequence formed by ANIQK by substituting one or several amino acids.
- the variant of EDLKN is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLNK.
- An amino acid sequence consisting of 1-3 amino acids; and/or a variant of ANIQK is an amino acid sequence consisting of 1-3 amino acids formed by deleting one or several amino acids of ANIQK.
- the variant of EDLKN is an amino acid sequence consisting of 6-12 amino acids formed by adding one or several amino acids to EDLKN (preferably at the N-terminus); and/or the variant of EDLNK is EDLNK after adding (preferably at the N-terminus) N-terminus) an amino acid sequence consisting of 6-12 amino acids formed by one or several amino acids; and/or the variant of ANIQK is ANIQK formed by adding (preferably at the N-terminus) one or several amino acids consisting of 6- An amino acid sequence consisting of 12 amino acids.
- the variants of EDLKN are EDL, DL, L, ED, E, D; and/or the variants of ANIQK are ANI, NI, I, AN, N, A, PNI, P, PN.
- the linkers in the polypeptide molecule are each independently 1 or 2-3 or more of the linkers. Head combination. In some embodiments, each linker in the polypeptide molecule is independently one or more of the linkers. In some embodiments, each linker in the polypeptide molecule is independently a combination of two or more of the linkers. In some embodiments, each linker in the polypeptide molecule is independently a combination of three or more of the linkers.
- the C-terminal of TRAV is connected to VH or VL through 2 linkers, and the proximal linker of TRAV is ANIQK or a variant thereof.
- a variant of ANIQK is an amino acid sequence formed by substituting, deleting, or adding one or several amino acids to ANIQK.
- the variant of ANIQK is the amino acid sequence formed by substituting one or several amino acids of ANIQK.
- the variant of ANIQK is an amino acid sequence consisting of 1-3 amino acids formed by deleting one or several amino acids of ANIQK, for example, ANI, NI, I, AN, N, A, PNI, P, PN.
- the C-terminal of TRBV is connected to VH or VL through two linkers, and the proximal linker of TRBV is EDLKN or a variant thereof, EDLNK or a variant thereof, ANIQK or a variant thereof.
- the variant of EDLKN is the amino acid sequence formed by EDLKN through substitution, deletion or addition of one or several amino acids; and/or the variant of EDLNK is the amino acid sequence of EDLNK through substitution, deletion or addition of one or several amino acids. formed amino acid sequence.
- the variant of EDLKN is an amino acid sequence formed by substituting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence formed by substituting one or several amino acids of EDLNK.
- the variant of EDLKN is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLNK.
- Amino acid sequence consisting of 1-3 amino acids for example, EDL, DL, L, ED, E, D.
- the C-terminus of TRAV is connected to TRAC through a linker, and the linker is ANIQK or a variant thereof.
- a variant of ANIQK is an amino acid sequence formed by substituting, deleting, or adding one or several amino acids to ANIQK.
- the variant of ANIQK is the amino acid sequence formed by substituting one or several amino acids of ANIQK.
- ANIQK variants are ANIQK amino acid sequences consisting of 1-3 amino acids formed by deleting one or several amino acids, for example, ANI, NI, I, AN, N, A, PNI, P, PN.
- the C-terminus of TRBV is connected to TRBC through a linker, and the linker is EDLKN or a variant thereof, or EDLNK or a variant thereof.
- the variant of EDLKN is the amino acid sequence formed by EDLKN through substitution, deletion or addition of one or several amino acids; and/or the variant of EDLNK is the amino acid sequence of EDLNK through substitution, deletion or addition of one or several amino acids. formed amino acid sequence.
- the variant of EDLKN is an amino acid sequence formed by substituting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence formed by substituting one or several amino acids of EDLNK.
- the variant of EDLKN is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLKN; and/or the variant of EDLNK is an amino acid sequence of 1-3 amino acids formed by deleting one or several amino acids of EDLNK.
- Amino acid sequence consisting of 1-3 amino acids for example, EDL, DL, L, ED, E, D.
- VH and VL comprise at least one cysteine mutation to form a disulfide bond between VH and VL, and the cysteine is introduced into FR4 in the case of VL and is introduced in the case of VH Introducing FR2.
- the cysteine mutations are at positions 44 of VH and 100 of VL.
- the TRAV and VL comprise at least one cysteine mutation to form a disulfide bond between TRAV and VL, preferably the cysteine mutation is at position 104 of TRAV bit and the 80th bit of VL.
- the TRBV and VL comprise at least one cysteine mutation to form a disulfide bond between TRBV and VL, preferably the cysteine mutation is at position 84 of TRBV bit and the 80th bit of VL.
- the TRAV and VH comprise at least one cysteine mutation to form a disulfide bond between TRAV and VH, preferably the cysteine mutation is at position 104 of TRAV position and VH's 89th.
- the TRBV and VH comprise at least one cysteine mutation To form a disulfide bond between TRBV and VH, preferably, the cysteine mutation is at the following positions: position 104 of TRBV and position 89 of VH.
- the TRAV may be native TRAV or a functional variant thereof, as long as the functional variant retains the ability to bind the target antigen.
- TRAV may be a truncated variant of native TRAV, such as a variant with 8 amino acids truncated at the N- or C-terminus.
- the TRBV may be native TRBV or a functional variant thereof, as long as the functional variant retains the ability to bind the target antigen.
- the TRAV and TRBV are those of an ⁇ TCR.
- the polypeptide molecule further contains a compound that can enhance its affinity or biological activity (e.g., enhance its solubility, enhance its aggregation, enhance its stability, extend its half-life, reduce its immunogenicity) or reduce its One or more amino acid mutations, insertions or deletions of post-translational modifications (eg glycosylation modifications), such as 1, 2, 3, 4, 5 or more amino acid mutations, insertions or deletions.
- Mutated, inserted or deleted amino acids include but are not limited to: (a) neutral amino acids: Ser, Gln; (b) acidic amino acids: Asp; (c) long-chain aliphatic amino acids: Ile; (d) short aliphatic amino acids: Alas, Gly.
- the amino acid mutations, insertions or deletions are located at the following amino acid positions: TRAV, TRBV, VL, beginning of VH, TRAV/TRAC junction amino acid, TRBV/TRBC junction amino acid, hinge region and adjacent amino acids , the boundary amino acid of CH2/CH3, the C terminus of CH3, and the amino acids near the linker.
- the amino acid mutations include mutations that enhance binding to FcRn and/or effector function silencing mutations.
- mutations capable of enhancing binding to FcRn include, for example, one or more of the following mutations: L234A, L235A, M252Y, S254T, T256E, M428L, N434S, T250R, M428L in the CH2 and CH3 domains , N434A, preferably L234AL235A, M252YS254TT256E, M428LN434S and T250RM428LN434A.
- the effector function silencing mutation is at one or more of the following positions of the CH2-CH3 domain: 233, 234, 235, 236, 297, and 331; preferably, the effector function silencing mutation is obtained by using Derived from substitution of at least one residue at positions 233, 234, 235, 236 and 331 with corresponding residues from IgG2 or IgG4.
- amino acid mutations that reduce post-translational modifications of the polypeptide molecule include, for example, N113K in TRAC and N210D in TRBC.
- the polypeptide molecule further comprises a signal peptide sequence at the N-terminus of one or both polypeptide chains, preferably a signal peptide sequence at the N-terminus of each chain, for example a signal peptide derived from albumin or immunoglobulin Sequence, preferably MGWSCIILFLVATATGVHS.
- the first antigen is a TAA selected from: melanoma associated antigens (e.g., gp100, MAGEA1, MAGEA3, MAGEA6, MAGEA4, MAGEA2, MAGEA12, MAGEA2B, MAGEA9B, MAGEA10, MAGEA11, MAGEB2, MAGEC1, MAGEC2), IGF2BP1, GNGT1, PI4K2B, CCR8, NPSR1, COX7B2, ONECUT3, SMC1B, FOXI3, GAGE2A, FBXO43, BRDT, PAGE2, GAGE13, POU5F1B, CTAG1A and endogenous reverse transcriptase antigens.
- melanoma associated antigens e.g., gp100, MAGEA1, MAGEA3, MAGEA6, MAGEA4, MAGEA2, MAGEA12, MAGEA2B, MAGEA9B, MAGEA10, MAGEA11, MAGEB2,
- the first antigen is a TSA selected from: KRAS (eg, G12D, G12V, G12C, G12R, G12A, G13D, Q61H, G125), TP53 (eg, R175H, R173H, R273C, R248W, R248Q , R282W, Y220C, V157F, G245S, Y163C, R249S), PIK3CA (such as E542K, E545K, H1047R), CTNNB1 (such as S45P, T41A), EGFR (such as L858R, T790M), BRAF (such as V600E) and GNAS (such as R201C , R201H).
- KRAS eg, G12D, G12V, G12C, G12R, G12A, G13D, Q61H, G125
- TP53 eg, R175H, R173H, R273C
- the first antigen is a viral antigen selected from the group consisting of: HPV E6 or E7 antigen, CMV antigen, HBV antigen, EBV antigen, herpes virus antigen, human immunodeficiency virus (HIV) antigen, influenza virus antigen and coronavirus antigens.
- the first antigen is an autoantigen selected from: AFP, CEA, CD19, CD20, BCMA, CD22, CD30, SLAM, CLDN18.2, GD2, mesothelin, CD38, Her2, GPC3 , MUC1, Ro52, Ro60, La, Jo-1, SRP, IFIH1, CENPA, CENPB, SNRPA1, SNRNP70, SNR-PD3, RNAP3, TOPO1, Insulin, GAD65, IA2, Znt8, PL7, TARS, ARS, MI2, topological heterogeneity Structural enzyme 1, EXOSC9, EXOSC107, POLR3A, POLR3K, PTRN, GAD2, SLC30A8, AchR, MUSK, LRP4, PLA2R, THSD7A, TSHR, IFN- ⁇ , CHRNA1, MUSK, LRP4, AQP4, MOG, GRIN1, COL4A3, PLA2R, GM-SCF, PR
- the second antigen is selected from the group consisting of CD3 (e.g., CD3 ⁇ , CD3 ⁇ , and CD3 ⁇ chains), CD4, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD25, CD32a, CD32b, CD41, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD61, CD64, CD68, CD94, CD90, CD117, Nkp46, NKG2D, Fc ⁇ RI, TCR ⁇ / ⁇ , TCR ⁇ / ⁇ , HLA-DR, CD28, 4-1BB(CD137), OX40 (CD134), ICOS (CD278), 2B4 (CD244), HVEM, LAG3, DAP10, DAP12, CD27, CD40, GITR, LFA-1, MyD88, CD2, CD7, LIGHT, B7-H3, CTLA-4, PD- 1. CD80, BTLA, TIM3, TIGIT and LAG-3.
- CD3
- the first antigen is a TAA selected from: melanoma associated antigens (e.g., gp100, MAGEA1, MAGEA3, MAGEA6, MAGEA4, MAGEA2, MAGEA12, MAGEA2B, MAGEA9B, MAGEA10, MAGEA11, MAGEB2, MAGEC1, MAGEC2), IGF2BP1, GNGT1, PI4K2B, CCR8, NPSR1, COX7B2, ONECUT3, SMC1B, FOXI3, GAGE2A, FBXO43, BRDT, PAGE2, GAGE13, POU5F1B, CTAG1A and endogenous reverse transcriptase antigen; and the second antigen is selected From CD3 (such as CD3 ⁇ , CD3 ⁇ and CD3 ⁇ chains), CD4, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD25, CD32a, CD32b, CD41, CD41b, CD42a
- CD3
- the first antigen is a TSA selected from: KRAS (eg, G12D, G12V, G12C, G12R, G12A, G13D, Q61H, G125), TP53 (eg, R175H, R173H, R273C, R248W, R248Q , R282W, Y220C, V157F, G245S, Y163C, R249S), PIK3CA (such as E542K, E545K, H1047R), CTNNB1 (such as S45P, T41A), EGFR (such as L858R, T790M), BRAF (such as V600E) and GNAS (such as R201C , R201H); and the second antigen is selected from the group consisting of CD3 (e.g., CD3 ⁇ , CD3 ⁇ , and CD3 ⁇ chains), CD4, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18
- CD3
- the first antigen is a viral antigen selected from the group consisting of: HPV E6 or E7 antigen, CMV antigen, HBV antigen, EBV antigen, herpes virus antigen, human immunodeficiency virus (HIV) antigen, influenza virus antigen and a coronavirus antigen; and the second antigen is selected from the group consisting of CD3 (e.g., CD3 ⁇ , CD3 ⁇ , and CD3 ⁇ chains), CD4, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD25, CD32a, CD32b, CD41, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD61, CD64, CD68, CD94, CD90, CD117, Nkp46, NKG2D, Fc ⁇ RI, TCR ⁇ / ⁇ , TCR ⁇ / ⁇ , HLA-DR, CD28, 4-1BB(CD137), OX40 (CD134), ICOS (CD278), 2B
- the first antigen is an autoantigen selected from: AFP, CEA, CD19, CD20, BCMA, CD22, CD30, SLAM, CLDN18.2, GD2, mesothelin, CD38, Her2, GPC3, MUC1, Ro52, Ro60, La, Jo-1, SRP, IFIH1, CENPA, CENPB, SNRPA1, SNRNP70, SNR-PD3, RNAP3, TOPO1, Insulin, GAD65, IA2, Znt8, PL7, TARS, ARS, MI2, topoisomerase 1, EXOSC9, EXOSC107, POLR3A, POLR3K, PTRN, GAD2, SLC30A8, AchR, MUSK, LRP4, PLA2R, THSD7A, TSHR, IFN- ⁇ , CHRNA1, MUSK, LRP4, AQP4, MOG, GRIN1, COL4A3, PLA2R, GM-SCF, PR3 and MPO; and the second autoantigen selected
- the first antigen is selected from gp100, MAGEA1, KRAS, and HPVE7.
- the second antigen is selected from CD3, CD28, and 4-1BB (CD137). In some embodiments, the second antigen is CD3. In some embodiments, the second antigen is CD28. In some embodiments, the second antigen is 4-1BB (CD137).
- the second antigen includes, but is not limited to, OKT3, UCHT-1, BMA031, and 12F6.
- the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-first linker-second linker-VH-linker-TRAC, and the second polypeptide chain from N-terminus to C-terminus End contains: VL-connector-TRBV-connector TRBC.
- the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-first linker-second linker-VH-linker-TRAC-hinge region-CH2-CH3, and the second polypeptide chain
- the peptide chain contains from N-terminus to C-terminus: VL-linker-TRBV-linker TRBC-hinge region-CH2-CH3.
- the first polypeptide chain comprises from N-terminus to C-terminus: TRAV-first linker-second linker-VH-linker-TRAC, and the second polypeptide chain from N-terminus to C-terminus The end contains: VL-connector-TRBV-connector TRBC-connector-ALB.
- the first antigen is gp100.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO: 1 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 1 % sequence identity to the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO:2 or having at least 80%, at least 85%, at least 90%, at least 95% identity with SEQ ID NO:2 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: a first polypeptide chain having an amino acid sequence shown in SEQ ID NO: 1, and a second polypeptide chain having an amino acid sequence shown in SEQ ID NO: 2 chain.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO:3 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:3 % sequence identity of the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO:4 or having at least 80%, at least 85%, at least 90%, at least 95% with SEQ ID NO:4 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: a first polypeptide chain having an amino acid sequence shown in SEQ ID NO: 3, and a second polypeptide chain having an amino acid sequence shown in SEQ ID NO: 4 chain.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO:5 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:5 % sequence identity to the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO: 6 or having at least 80%, at least 85%, at least 90%, at least 95% with SEQ ID NO: 6 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: having an amino group as shown in SEQ ID NO:5 A first polypeptide chain having an amino acid sequence, and a second polypeptide chain having an amino acid sequence as shown in SEQ ID NO: 6.
- the first antigen is KRAS.
- TRAV in the polypeptide molecule, includes CDR1 represented by NSASQS (SEQ ID NO:89), CDR2 represented by VYSSGN (SEQ ID NO:90), and VVPGGTGGGNKLT (SEQ ID NO:91) CDR3 shown; TRBV contains CDR1 shown by LGHDT (SEQ ID NO:92), CDR2 shown by YNNKEL (SEQ ID NO:93), and CDR3 shown by ASSHWGAQETQY (SEQ ID NO:94).
- TRAV comprises RKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCVVPGGTGGGNKLTFGTQLKVEL (SEQ ID NO:95). In some embodiments, TRAV comprises RKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCVVPGGTGGGNKLTFGGTQLPVPL (SEQ ID NO:96).
- TRAV comprises RKIVEQDPGPFEVPEGATVAFICTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQDIHLLIRDSKLSDSATYLCVVPGGTGGGNKLTFGGTQLPVPL (SEQ ID NO:97).
- TRBV comprises DTAVSQTPKYLVTQMGNDKSIKCEQNLGHDTMDWYKQDSKKFLKIMFSYNNKELIINETVPNRFSPKSPDKAHLNLHINSLELGDSAVYFCASSHWGAQETQYFPGGTRLLVL (SEQ ID NO:98).
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO:99 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:99 % sequence identity to the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO: 100 or having at least 80%, at least 85%, at least 90%, at least 95% identity with SEQ ID NO: 100 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: a first polypeptide chain having an amino acid sequence shown in SEQ ID NO: 99, and a second polypeptide chain having an amino acid sequence shown in SEQ ID NO: 100 chain.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO: 101 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 101 % sequence identity to the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO: 102 or having at least 80%, at least 85%, at least 90%, at least 95% identity with SEQ ID NO: 102 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: a first polypeptide chain having an amino acid sequence shown in SEQ ID NO: 101, and a second polypeptide chain having an amino acid sequence shown in SEQ ID NO: 102 chain.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO: 103 or at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 103 % sequence identity to the first polypeptide chain of the amino acid sequence, and having an amino acid sequence as shown in SEQ ID NO: 104 or having at least 80%, at least 85%, at least 90%, at least 95% identity with SEQ ID NO: 104 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: a first polypeptide chain having the amino acid sequence shown in SEQ ID NO: 103, and a second polypeptide having the amino acid sequence shown in SEQ ID NO: 104 chain.
- the polypeptide molecule comprises: having an amino acid sequence as set forth in SEQ ID NO: 105 or being at least 80%, at least 85%, at least 90%, at least 95%, or at least 99 identical to SEQ ID NO: 105 % sequence identity to a first polypeptide chain of an amino acid sequence, and having an amino acid sequence as set forth in SEQ ID NO: 106 or having at least 80%, at least 85%, at least 90%, at least 95% identity with SEQ ID NO: 106 or a second polypeptide chain having an amino acid sequence of at least 99% sequence identity.
- the polypeptide molecule comprises: having SEQ ID NO:105 A first polypeptide chain having the amino acid sequence shown in SEQ ID NO: 106, and a second polypeptide chain having the amino acid sequence shown in SEQ ID NO: 106.
- the first antigen is MAGE-A1.
- TRAV comprises RGEDVEQSLFLSVREGDSSVINCTYTDSSSSTYLYWYKQEPGAGLQLLTYIFSNDMMKQDQRLTVLLNKKDKHLSLRIADTQTGDSAIYFCAGSGGGTDKLIFGGTRLQVFPN (SEQ ID NO: 107).
- TRAV comprises RGEDVEQSLFLSVREGDSSVINCTYTDSSSSTYLYWYKQEPGAGLQLLTYTWPHMDMKQDQRLTVLLNKKDKHLSLRIADTQTGDSAIYFCAGSGGGTDKLIFGGTRLQVFPN (SEQ ID NO: 108).
- TRBV comprises GAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSDYQTCVTYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSAREPGQGPFEQYFPGGTRLTVTE (SEQ ID NO: 109).
- TRBV comprises GAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSAREPGQGPYEQYFPGGTRLTVTE (SEQ ID NO: 110).
- the first antigen is an HPV antigen, such as HPV E7.
- TRAV in the polypeptide molecule, includes CDR1 represented by NSASQS (SEQ ID NO:111), CDR2 represented by VYSSGN (SEQ ID NO:112), and AVISAGTALI ( CDR3 shown in SEQ ID NO:113); TRBV contains CDR1 shown in SGHDT (SEQ ID NO:114), CDR2 shown in YYEEEE (SEQ ID NO:115), and ASSLGWRGGLYTEAF (SEQ ID NO:116) CDR3.
- NSASQS SEQ ID NO:111
- CDR2 represented by VYSSGN
- AVISAGTALI CDR3 shown in SEQ ID NO:113
- TRBV contains CDR1 shown in SGHDT (SEQ ID NO:114), CDR2 shown in YYEEEE (SEQ ID NO:115), and ASSLGWRGGLYTEAF (SEQ ID NO:116) CDR3.
- TRAV comprises RKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDG RFTAQLNRASQYISLLIRDSKLSDSATYLCAVISAGTALIFGKGTTLSVSS (SEQ ID NO: 117).
- TRBV comprises DAGVTQSPTHLIKTRGQQVTLRCSPKSGHDTVSWYQQALGQGPQFIFQYYEEEERQRGNFPDRFSGHQFPNYSSELNVNALLLGDSALYLCASSLGWRGGLYTEAFFGQGTRLTVV (SEQ ID NO: 118).
- the invention provides a T cell receptor (TCR) comprising a TCR alpha chain variable region (TRAV) and a TCR beta chain variable region (TRBV), wherein the TRAV comprises a TCR alpha chain variable region (TRAV), respectively, as shown in SEQ ID NO: 89 , CDR1, CDR2 and CDR3 of the amino acid sequences shown in SEQ ID NO:90 and SEQ ID NO:91, or functional variants formed by inserting, deleting or replacing one or several amino acids; and/or the TRBV contains respectively ⁇ -chain CDR1, CDR2 and CDR3 having the amino acid sequences shown in SEQ ID NO:92, SEQ ID NO:93 and SEQ ID NO:94, or functional variants formed by inserting, deleting or replacing one or several amino acids .
- TCR T cell receptor
- TRBV TCR alpha chain variable region
- the TRAV comprises CDR1, CDR2 and CDR3 having the amino acid sequences set forth in SEQ ID NO:89, SEQ ID NO:90 and SEQ ID NO:91 respectively; and/or the TRBV comprises respectively Beta chain CDR1, CDR2 and CDR3 having the amino acid sequences shown in SEQ ID NO:92, SEQ ID NO:93 and SEQ ID NO:94.
- the TRAV comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to SEQ ID NO: 95, and/or the TRBV comprises SEQ ID NO:98 An amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity.
- the TRAV comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to SEQ ID NO: 96, and/or the TRBV comprises SEQ ID NO:98 An amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity.
- the TRAV comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to SEQ ID NO: 97, and/or the TRBV comprises SEQ ID NO:98 An amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity.
- the invention provides a nucleic acid comprising a nucleotide sequence encoding each strand of a bispecific polypeptide molecule of the invention.
- the invention also provides nucleic acids comprising a nucleotide sequence encoding the TCR of the invention.
- the invention provides a vector comprising a nucleic acid according to the invention.
- vectors include, but are not limited to, plasmids, viral vectors (including retroviral vectors, lentiviral vectors, adenoviral vectors, vaccinia virus vectors, polyomavirus vectors, and adenovirus-associated vectors (AAV)), phages, phagemids, Cosmids and artificial chromosomes (including BAC and YAC).
- viral vectors including retroviral vectors, lentiviral vectors, adenoviral vectors, vaccinia virus vectors, polyomavirus vectors, and adenovirus-associated vectors (AAV)
- phages phagemids
- Cosmids and artificial chromosomes including BAC and YAC.
- the vector itself is usually a nucleotide sequence, usually a DNA sequence containing the insert (transgene) and a larger sequence that serves as the "backbone" of the vector.
- Engineered vectors typically contain an origin of autonomous replication in the host cell (if stable expression of the polynucleotide is desired), a selectable marker, and a restriction enzyme cleavage site (such as a multiple cloning site, MCS).
- the vector may additionally contain a promoter, genetic marker, reporter gene, targeting sequence, and/or protein purification tag.
- suitable vectors are provided in J. Sambrook et al., Molecular Cloning: A Laboratory Manual (4th ed.), Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, New York (2012), which is incorporated herein by reference in its entirety.
- the vector is preferably selected from the group consisting of lentiviral vectors, retroviral vectors, plasmids, DNA vectors, mRNA vectors, transposon-based vectors, and artificial chromosomes.
- the invention provides a vector system comprising on one or more vectors encoding the invention.
- the nucleotide sequence of each chain of the bispecific polypeptide molecule is provided.
- the invention provides a host cell comprising a nucleic acid, vector or vector system of the invention.
- the cells may be eukaryotic cells, such as plants (without the potential to develop into plants), animals, fungi or algae, or may be prokaryotic cells, such as bacteria or protozoa.
- the cells may be cultured cells or primary cells, ie, isolated directly from an organism, such as a human. Cells can be adherent cells or suspension cells, that is, cells grown in suspension. Suitable host cells are known in the art and include, for example, DH5 ⁇ E. coli cells, Chinese hamster ovary cells, monkey VERO cells, COS cells, HEK293 cells, and the like.
- the cells are preferably mammalian cells. Most preferably, the host cells are human cells.
- the cells are selected from lymphocytes (eg, T cells, NK cells), monocytes (eg, PBMCs), and stem cells.
- the stem cells may be lymphoid progenitor cells, induced pluripotent stem cells (iPSCs), or hematopoietic stem cells (HSCs).
- iPSCs induced pluripotent stem cells
- HSCs hematopoietic stem cells
- stem cells do not include embryonic stem cells obtained by destroying human embryos, and/or do not include totipotent stem cells used to develop and form an animal individual.
- the invention provides conjugates comprising a bispecific polypeptide molecule of the invention, and a chemical moiety conjugated to the bispecific polypeptide molecule.
- the invention also provides conjugates comprising the TCR of the invention, and a chemical moiety conjugated to the TCR.
- the chemical moiety is selected from the group consisting of therapeutic agents, immunostimulatory molecules, and detectable labels.
- therapeutic agents include, but are not limited to, immunomodulators, radioactive compounds, enzymes (eg, perforin), chemotherapeutic agents (eg, cisplatin), or toxins.
- the therapeutic agent may be, for example, maytansine, geldanamycin, a tubulin inhibitor such as a tubulin binding agent (such as auristatins) or a minor groove binding agent such as calicheamicin (calicheamicin).
- cytotoxic agents include, for example, small molecule cytotoxic agents, ie, compounds with a molecular weight of less than 700 daltons that have the ability to kill mammalian cells. Such compounds may also contain toxic metals that can have cytotoxic effects. Furthermore, it should be understood that these small molecule cytotoxic agents also include prodrugs, i.e., compounds that break down or transform under physiological conditions to release the cytotoxic agent.
- agents include cisplatin, maytansine derivatives, racithromycin, calicheamicin, docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, melphalan, Mitoxantrone, sorfimer porphyrin sodium II, temozolomide, topotecan, metformin, auristatin E, vinca alkaloids, and doxorubicin; peptide cytotoxins, i.e., proteins with the ability to kill mammalian cells or Fragments thereof, such as ricin, diphtheria toxin, Pseudomonas bacterial exotoxin A, DNase and RNase; radionuclides, i.e., with the simultaneous emission of one or more alpha or beta particles or gamma rays Unstable isotopes of decaying elements, such as iodine-131, rhenium-186, indium-111,
- the immunostimulatory molecule is an immune effector molecule that stimulates an immune response.
- the immunostimulatory molecule may be a cytokine such as IL-2 and IFN- ⁇ , a chemokine such as IL-8, platelet factor 4, melanoma growth stimulating protein, complement activator; viral/bacterial protein domain, or viral/ Bacterial peptides.
- the immunostimulatory molecule is selected from the group consisting of cytokines, chemokines, platelet factors and complement initiators.
- the detectable label can be selected from biotin, streptavidin, enzymes or catalytically active fragments thereof, radionuclides, nanoparticles, paramagnetic metal ions, or fluorescent, phosphorescent, or chemiluminescent molecules.
- Detectable moieties for diagnostic purposes include, for example, fluorescent labels, radioactive labels, enzymes, nucleic acid probes, and contrast agents.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the bispecific polypeptide molecule, nucleic acid, vector, vector system, host cell, or conjugate of the invention, and a pharmaceutically acceptable excipient.
- compositions of the present invention are particularly suitable for administration to humans; however, they are also suitable for administration to non-human animals.
- the compounds and their components i.e., active agents and optional excipients
- Pharmaceutical compositions of the invention may, for example, be sterile.
- excipients include, but are not limited to, fillers, binders, disintegrants, coating agents, adsorbents, anti-adhesive agents, glidants, preservatives, antioxidants, flavoring agents, colorants, sweetening agents agents, solvents, co-solvents, buffers, chelating agents, viscosity imparting agents, surfactants, diluents, wetting agents, carriers, diluents, preservatives, emulsifiers, stabilizers and tonicity regulators. It is known to those skilled in the art to select suitable excipients for the preparation of pharmaceutical compositions of the invention.
- Exemplary carriers for use in pharmaceutical compositions of the present invention include saline, buffered saline, dextrose, and water.
- saline aline
- buffered saline aline
- the pharmaceutical composition of the present invention can be prepared into various forms, such as solid, liquid, gaseous or freeze-dried forms, especially ointments, creams, transdermal patches, gels, in the form of a powder, tablet, solution, aerosol, granule, pill, suspension, emulsion, capsule, syrup, liquid, elixir, extract, tincture or liquid extract, or Particularly suitable for the form of application required.
- Processes for producing pharmaceuticals known in this invention are shown in Remington's Pharmaceutical Sciences, 22nd Edition (Ed. Maack Publishing Co, Easton, Pa., 2012), and may include, for example, conventional mixing, dissolving, granulating, sugar-coating, Grinding, emulsifying, encapsulating, embedding or freeze-drying processes.
- the pharmaceutical composition further comprises a second therapeutic agent, preferably the second therapeutic agent is selected from the group consisting of antibodies, chemotherapeutic agents and small molecule drugs.
- the second therapeutic agent include known anticancer drugs such as cisplatin, maytansine derivatives, rachelmycin, calicheamicin, docetaxel, etoposide, Gemcitabine, ifosfamide, irinotecan, melphalan, mitoxantrone, sorfimer sodium photofrin II (sorfimer sodium photofrin II), temozolomide, topotecan, trimetreate glucuronate (trimetreate glucuronate), olefin auristatin E, vincristine, and doxorubicin; and peptide cytotoxins, such as ricin, diphtheria toxin, Pseudomonas bacterial exotoxin A, DNase, and RNase; radionuclides, such as iodine 131, rhenium 186, indium 111, iridium 90, bismuth 210 and 213, actinium 225 and asta
- the invention provides a method for preventing or treating a disease in a subject, comprising administering to the subject an effective amount of the bispecific polypeptide molecule, TCR, nucleic acid, vector, vector of the invention A system, host cell, conjugate, or pharmaceutical composition, wherein the disease is selected from the group consisting of cancer, infectious diseases, autoimmune diseases, and inflammatory diseases.
- the cancer may be any cancer, such as cancer of the blood system, cancer of the central and peripheral nervous system, cancer of the lymphatic lineage, cancer of the myeloid lineage, cancer of mesenchymal origin, solid tumors, etc.
- cancers include, but are not limited to, acute lymphoblastic cancer, acute myelogenous leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, anal cancer, anal canal or anorectal cancer, eye cancer, intrahepatic bile duct Cancer, joint cancer, neck cancer, gallbladder or pleural cancer, nose cancer, nasal cavity or middle ear cancer, oral cancer, vaginal cancer, vulvar cancer, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer Carcinoma, gastrointestinal carcinoid tumors, glioma, Hodgkin lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer
- Infectious diseases are diseases caused by pathogenic infections, including communicable diseases and non-communicable diseases. cause
- the pathogens of infectious diseases include viruses, bacteria, mycoplasma, chlamydia, rickettsiae, prions, fungi, spirochetes and parasites.
- viruses include, but are not limited to, HPV, CMV, HBV, EBV, herpes viruses, human immunodeficiency virus (HIV), influenza viruses, and coronaviruses.
- autoimmune and inflammatory diseases include but are not limited to rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, diabetes caused by autoimmune destruction of pancreatic islets, Sjogren's syndrome, Hashimoto's thyroid inflammatory bowel disease, Graves' thyroiditis, toxic diffuse goiter, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), psoriasis, glomerulonephritis , nephrotic syndrome, anti-glomerular basement membrane disease, membranous nephropathy, systemic sclerosis, polymyositis, myasthenia gravis, psoriasis, pemphigus, vitiligo, autoimmunity of the central nervous system Diseases, celiac disease, autoimmune gastritis, primary bili
- the dosage administered to a subject may vary depending on the embodiment, the agent used, the method of administration, and the site and subject being treated. However, the dose should be sufficient to provide a therapeutic response. Clinicians can determine an effective amount for administration to a human or other subject to treat a medical condition. The precise amount required for the treatment to be effective may depend on many factors, such as the activity of the active agent and the route of administration.
- the dose of the polypeptide molecule, conjugate or pharmaceutical composition of the invention can be administered to the mammal once or in a series of sub-doses over a suitable period of time, for example, daily, every half week, every week, every day as needed. Apply biweekly, semimonthly, bimonthly, semiannually, or annually. Dosage units containing an effective amount of a polypeptide molecule, conjugate or pharmaceutical composition may be administered in a single daily dose, or the total daily dose may be administered in two, three, four or more doses per day as desired. Give in divided doses.
- the appropriate method of administration can be chosen by the physician.
- the route of administration may be parenteral, for example by injection, nasal administration, pulmonary administration or transdermal administration.
- Systemic or local administration can be by intravenous injection, intramuscular injection, intraperitoneal injection, or subcutaneous injection.
- the polypeptide molecule, conjugate, or pharmaceutical composition is selected for parenteral delivery, inhalation, or delivery through the gastrointestinal tract, such as orally.
- the dosage and method of administration may vary according to the subject's weight, age, condition, etc., and may be appropriately selected.
- the method further includes administering a second therapeutic agent to the subject.
- a polypeptide molecule, conjugate, or pharmaceutical composition of the invention is administered before, substantially simultaneously with, or after the second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of antibodies, chemotherapeutic agents and small molecule drugs. Preferred examples of second therapeutic agents are as described above.
- the present disclosure provides a method of detecting (e.g., diagnosing) a disease in a subject, wherein the method comprises (i) conjugating a sample obtained from the subject with a polypeptide molecule, TCR or conjugate of the invention contact; and (ii) detecting the presence of a target antigen in the sample, wherein the presence of the target antigen indicates that the subject suffers from the corresponding disease.
- Target antigens can be selected from tumor-associated antigens (TAA), tumor-specific antigens (TSA), viral antigens and autoantigens.
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- the disease may be selected from cancer, infectious diseases, autoimmune diseases and inflammatory diseases.
- the target antigen is KRAS.
- the antigen is MGAE-A1.
- the cancers, infectious diseases, autoimmune diseases and inflammatory diseases are as defined above.
- the sample obtained from the subject may be a blood sample, urine sample, tissue sample, or cell sample.
- the methods are performed in vitro.
- the method includes (i) contacting a sample obtained from a subject with a conjugate of the invention, wherein the conjugate comprises a detectable label; and (ii) by detecting the detectable label. The sample is detected for the presence of the target antigen.
- detectable labels include, but are not limited to, biotin, streptavidin, enzymes or catalytically active fragments thereof, radionuclides, nanoparticles, paramagnetic metal ions, Nucleic acid probes, contrast agents, and fluorescent, phosphorescent or chemiluminescent molecules; preferably enzymes or catalytically active fragments thereof, radionuclides, fluorescent, phosphorescent or chemiluminescent molecules.
- the disclosure provides a kit comprising a polypeptide molecule, TCR or conjugate of the disclosure for detecting the presence of a target antigen in a sample to be tested.
- the kit is a kit for detecting (eg, diagnosing) a disease in a subject, comprising a polypeptide molecule or conjugate of the disclosure.
- Target antigens can be selected from tumor-associated antigens (TAA), tumor-specific antigens (TSA), viral antigens and autoantigens.
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- the disease may be selected from cancer, infectious diseases, autoimmune diseases and inflammatory diseases.
- the cancers, infectious diseases, autoimmune diseases and inflammatory diseases are as defined above.
- the conjugate includes a detectable label.
- detectable labels include, but are not limited to, biotin, streptavidin, enzymes or catalytically active fragments thereof, radionuclides, nanoparticles, paramagnetic metal ions, nucleic acid probes, contrast agents, and fluorescent, phosphorescent Or chemiluminescent molecules; preferably enzymes or catalytically active fragments thereof, radionuclides, fluorescent, phosphorescent or chemiluminescent molecules.
- the kit may also include instructions on how to use the kit.
- the present disclosure provides bispecific polypeptide molecules, TCRs, nucleic acids, vectors, vector systems, host cells, conjugates or pharmaceutical compositions of the invention for use in the treatment or prevention of disease in a subject. Uses in medicines.
- the disclosure provides a bispecific polypeptide molecule, TCR, nucleic acid, vector, vector system, host cell, conjugate or pharmaceutical composition of the invention for use in treating or preventing a disease in a subject .
- the disclosure provides the use of a bispecific polypeptide molecule, TCR or conjugate of the invention in the preparation of a kit for detecting the presence of a target antigen in a sample to be tested.
- the present disclosure provides the use of a bispecific polypeptide molecule, TCR, or conjugate of the invention in the preparation of a kit for detecting (eg, diagnosing) a disease in a subject.
- the disclosure provides a bispecific polypeptide molecule, TCR or conjugate of the invention for use in detecting the presence of a target antigen in a sample to be tested.
- the target antigen may be selected from the group consisting of tumor-associated antigens (TAA), tumor-specific antigens (TSA), viral antigens, and autoantigens.
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- viral antigens and autoantigens.
- the disease may be selected from cancer, infectious diseases, autoimmune diseases and inflammatory diseases.
- the cancers, infectious diseases, autoimmune diseases and inflammatory diseases are as defined above.
- Figure 1 shows the structural schematic diagram, AlphaFold2 diagram, immunoblotting result diagram and ELISPOT assay result diagram of a specific form of format 22-2 of the present invention.
- Figure 2 shows a schematic structural diagram, an immunoblotting result diagram and an ELISPOT assay result diagram of a specific form of format 64 of the present invention.
- Figure 3 shows a schematic structural diagram of a specific form of format 63 of the present invention.
- Figure 4 shows a schematic structural diagram of a specific form of control format 17, protein staining and immunoblotting results, and ELISPOT assay results.
- Figure 5 shows a schematic structural diagram of a specific form of control format 22, protein staining and immunoblotting results, and ELISPOT assay results.
- Figure 6 shows the ELISPOT measurement results of format 22-2 of the present invention when KRAS is used as the target peptide.
- TCR-based bispecific peptide molecules format 22-2 (such as the first chain shown in SEQ ID NO: 1 and the second chain shown in SEQ ID NO: 2), format 64 (such as The first strand as shown in SEQ ID NO:3 and the second strand as shown in SEQ ID NO:4) and format 63 (the first strand as shown in SEQ ID NO:5 and the first strand as shown in SEQ ID NO:6 The second chain), the structures of these formats are shown in Figure 1-3. The three-dimensional structure diagrams of these formats are also displayed through AlphaFold2.
- formats 17 and 22 were also constructed as controls.
- the TRAC and TRBC of the format 22-2 of the present invention are replaced with the hinge region-CH2-CH3, which is Format 17; the TRAC and TRBC of the format 22-2 of the present invention are replaced with CH3, which is Format 22.
- the structure of Format 17 is: the first polypeptide chain contains from N-terminus to C-terminus: TRAV-linker-VH-optional linker-hinge region-CH2-CH3, and the second polypeptide chain contains from N-terminus to C-terminus :VL-linker-TRBV-optional linker-hinge region-CH2-CH3.
- the structure of Format 22 is: the first polypeptide chain from N-terminus to C-terminus contains: TRAV-linker-VH-optional linker-CH3, and the second polypeptide chain from N-terminus to C-terminus contains: VL-linker- TRBV-optional linker-CH3.
- the structural diagrams of Format 17 and Format 22 are shown in Figure 4 and Figure 5 respectively.
- amino acid sequence components used in these formats are as follows:
- >TRBC1 contains S57C, C187A, N210D mutations
- >TRBC1 contains S57C, C187A, N210D, and FG loop deletion mutations
- CH2-CH3 Hole (contains T366S, L368A and Y407V hole mutations and Y349C mutation)
- amino acid sequences of the two polypeptide chains of control format 17 are as follows:
- amino acid sequences of the two polypeptide chains of control format 22 are as follows:
- the signal peptide sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 66) is added to the N-terminus of each polypeptide chain of these formats to increase the secretion of the polypeptide molecules, and a His6 tag is added to the C-terminus of any chain of the format for purification.
- the format in this example can bind to the complex of gp100 epitope YLEPGPVTA (SEQ ID NO: 67) or its mutant form (YLEPGPVTV, SEQ ID NO: 68)) and HLA-A*02.
- the multispecific polypeptide molecule format targeting KRAS was constructed as described in Example 1.1.
- KRAS-targeting foramt 22-2 molecules KVA11-N03_B22-2_WT (the amino acid sequences of its two chains are shown in SEQ ID NO:99 and 100 respectively), KVA11-N03_B22-2_Mut1 (these The amino acid sequences of the two chains are shown in SEQ ID NO:101 and 102 respectively), KVA11-N03_B22-2_Mut2 (the amino acid sequences of the two chains are shown in SEQ ID NO:103 and 104 respectively), KVA11-N03_B22-2_Mut3 (The amino acid sequences of its two chains are shown in SEQ ID NO: 105 and 106 respectively).
- the format in this example can bind to the complex of KRAS epitope VVGAVGVGK (SEQ ID NO: 119) and HLA-A*11.
- the multispecific polypeptide molecule format targeting MAGEA1 was constructed as described in Example 1.1.
- the structure of the format is the same as that in Example 1.1. The only difference is that the gp100-specific TCR in Example 1.1 was replaced with TRAV and TRBV of MAGEA1-specific TCR. TRAV and TRBV.
- the amino acid sequences of TRAV and TRBV of the MAGEA1-specific TCR are as follows:
- the format in this example can bind to the complex of MAGEA1 epitope KVLEYVIKV (SEQ ID NO: 120) and HLA-A*02.
- the nucleotide sequence encoding one or more polypeptide chains of the format in Example 1 is directly cloned into the expression vector pTT5.
- the obtained vector clone is confirmed by sequencing and then amplified, cultured, and plasmid extracted.
- transfection solution (1ml): Dilute 10 ⁇ g DNA with about 800 ⁇ L of 150mM sterilized NaCl solution, mix well and place it on the workbench for 5 minutes; add about 50 ⁇ l of transfection reagent to the DNA diluent and mix well to obtain the final transfection solution. The total volume is 1mL.
- the collected culture supernatant was used for nickel column purification. Prepare a 1ml packed nickel column, rinse with 10ml sterile water, and balance with 10ml 1XBind Buffer. The culture supernatant was centrifuged at 3000 rpm for 5 min, then filtered with chlorine gas at 450 nm, and loaded. After loading the sample, wash the column with 10ml 1XBind Buffer, wash the column with 10ml 1XBind Buffer, wash the column with 10ml 1XWash Buffer (collect 10 tubes of eluate, the flow rate is around 0.3-0.4ml/min), and elute the protein with 1.2ml 1XElution Buffer. Collect the eluate to obtain the purified protein, aliquot and store at -80°C.
- the purified protein was denatured (R) or non-denatured (NR) and then subjected to SDS-PAGE gel electrophoresis and Coomassie brilliant blue staining to evaluate the protein expression purity and degree of aggregation.
- Another set of parallel samples were subjected to gel electrophoresis and then subjected to western blotting.
- Mouse anti-His6 was used as the primary antibody to detect the His6 tag of the purified protein to confirm the reliability of Coomassie brilliant blue staining. The results show that the format provided by the invention can be successfully expressed.
- Exemplary western blot results are shown in Figures 1 and 2.
- the concentration of the target protein is predicted based on the harvested target protein yield, and the purity is determined based on the SDS-PAGE Coomassie Brilliant Blue staining results. It can be seen that the format provided by the present invention can be successfully expressed.
- Example 2 of the present invention The culture supernatant collected in Example 2 of the present invention is subjected to gradient dilution (usually 2-fold dilution and 5-fold dilution are used). Then the corresponding target peptide and non-related peptide were added to DMSO to dissolve, and diluted with water to a usage concentration of 10-4M. T2 cells were used to load 10-6M of target peptide and irrelevant peptide respectively. Add 1640 complete medium containing 10% FBS to the ELISPOT plate and block for 30 min at room temperature.
- the secretion of IFN- ⁇ was determined by ELISPOT detection to evaluate the immune cell activation induced by the format of the present invention through the target antigen peptide-MHC complex.
- results show that the format of the present invention can activate immune cells in the presence of target antigen, but cannot activate immune cells when adding irrelevant target peptides or in the negative control group without adding polypeptides.
- FIG. 6 Exemplary results of the format of the present invention are shown in Figure 6, in which the culture supernatant of format 22-2 with different amino acid sequences can activate immune cells at both 2-fold and 5-fold dilution.
- Example 1 of the present invention was gradient diluted (10 -7 to 10 -13 M) with 1640 complete culture medium containing 10% FBS. Add gp100 polypeptide, KRAS polypeptide, and MAGE-A1 polypeptide to DMSO to dissolve respectively, and then dilute with water to a usage concentration of 10 -4 M. T2 cells were used to load 10 -6 M gp100 polypeptide, HPV E7 polypeptide, and MAGE-A1 polypeptide respectively. Add 1640 complete medium containing 10% FBS to the ELISPOT plate and block for 30 min at room temperature.
- Exemplary results of the format of the present invention are shown in Figures 1 and 2 (the reference mark “+” indicates the experimental group in which gp100 polypeptide was added, “-” indicates the negative control group in which gp100 polypeptide was not added, and “irrelevant” indicates the addition of gp100 polypeptide.
- the results of control formats 17 and 22 are shown in Figures 4 and 5 respectively (the reference mark “+” indicates the experimental group in which gp100 polypeptide was added, and "-” indicates the negative control group in which gp100 polypeptide was not added).
- format 22-2 and format 64 of the present invention can achieve effective activation of immune cells in the concentration range of 10 -7 -10 -10 M and 10 -7 -10 -9 M respectively, especially format 22-2 Immune cells can be effectively activated at a low concentration of 10 -10 M ( Figure 1), while control formats 17 and 22 require a higher concentration of 10 -8 M to activate immune cells ( Figures 4 and 5), indicating that this The invented format has a significantly better activation effect on immune cells than the control formats 17 and 22. This suggests that TRAC and TRAC used in the format of the present invention have significantly better effects than using the CH3 or hinge region-CH2-CH3 of the antibody when combined with specific first and second antigen-binding regions.
- Example 1 of the present invention was serially diluted (10 -7 to 10 -13 M) with 1640 complete culture medium containing 10% FBS. Add gp100 polypeptide, KRAS polypeptide, and MAGE-A1 polypeptide to DMSO to dissolve respectively, and then dilute with water to a usage concentration of 10 -4 M. T2 cells were loaded with 10 -6 M of target polypeptide. Add 5x10 5 cells/mL PBMC (100 ⁇ L/well), 5x10 4 cells/mL polypeptide-loaded T2 cells (100 ⁇ L/well), and different concentrations of format (10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 M).
- T2 cells and PBMC not loaded with gp100 polypeptide were added. After adding all samples, cover the plate and place it in a 37°C, 5% CO2 incubator for 20-24 hours. Discard the supernatant and add 100 ⁇ L of the detection solution of the luciferase reporter gene quantitative assay kit to detect the target cells. Luciferase activity to assess killing of target cells. Based on the target cell killing data, nonlinear regression was used to calculate the EC50 of each format for target cell killing using GraphPad software.
- the results show that the format provided by the present invention can kill target cells in the concentration range of 10 -7 -10 -10 M or even lower.
- the prepared expression plasmids containing TCR ⁇ -chain and ⁇ -chain were each transformed into E. coli strain Rosetta (DE3) pLysS, protein expression was induced, inclusion bodies were harvested, inclusion bodies were dissolved with a denaturant, and then dialyzed, renatured, and purified. Purified TCR-based multispecific polypeptide molecules provided by the invention are obtained.
- the TCR-based multispecific polypeptide molecules provided by the present invention have a KD that binds to MHC-polypeptide complexes less than or equal to 1 ⁇ M and/or a koff of 1 ⁇ 10-3S-1 or slower, and a KD that binds to T cell surface molecules is less than or equal to 1 ⁇ M and/or koff is 1 ⁇ 10-3S-1 or slower.
- TCR-based multispecific polypeptide molecules of the present invention The killing of transplanted tumors by the TCR-based multispecific polypeptide molecules of the present invention is determined to evaluate its tumor suppressive effect in vivo.
- the TCR-based multispecific polypeptide molecules provided by the present invention have anti-tumor efficacy in vivo.
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Abstract
La présente invention concerne une molécule polypeptidique bispécifique à base de récepteur de lymphocytes T et son utilisation. La présente invention concerne en outre un acide nucléique codant pour la molécule polypeptidique selon la présente invention, un vecteur ou un système vecteur comprenant l'acide nucléique selon la présente invention, une cellule hôte comprenant la molécule polypeptidique selon la présente invention, un conjugué et une composition pharmaceutique comprenant la molécule polypeptidique selon la présente invention, et une méthode de prévention ou de traitement d'une maladie chez un sujet à l'aide de la molécule polypeptidique selon la présente invention.
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PCT/CN2023/102211 WO2023246943A1 (fr) | 2022-06-24 | 2023-06-25 | Molécule polypeptidique multispécifique à base de récepteurs de cellules t et son utilisation |
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WO2019057124A1 (fr) * | 2017-09-22 | 2019-03-28 | Wuxi Biologics (Shanghai) Co., Ltd. | Nouveaux complexes polypeptidiques cd3/cd19 bispécifiques |
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GB0911566D0 (en) * | 2009-07-03 | 2009-08-12 | Immunocore Ltd | T cell receptors |
TWI788286B (zh) * | 2016-04-13 | 2023-01-01 | 法商賽諾菲公司 | 三特異性和/或三價結合蛋白 |
JP7387611B2 (ja) * | 2017-09-22 | 2023-11-28 | ウーシー バイオロジクス アイルランド リミテッド | 新規二重特異性ポリペプチド複合体 |
BR112020007002A2 (pt) * | 2017-10-10 | 2020-11-17 | Sanofi | anticorpos anti-cd38 e métodos de uso |
US20210361704A1 (en) * | 2018-03-09 | 2021-11-25 | TCR2 Therapeutics Inc. | Compositions and methods for tcr reprogramming using fusion proteins |
KR20210075129A (ko) * | 2018-10-09 | 2021-06-22 | 사노피 | 삼중특이적 항-cd38, 항-cd28, 및 항-cd3 결합 단백질 및 바이러스 감염을 치료하기 위한 사용 방법 |
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