WO2025131027A1 - Anticorps anti-slc34a2/anti-4-1bb et leurs utilisations - Google Patents

Anticorps anti-slc34a2/anti-4-1bb et leurs utilisations Download PDF

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WO2025131027A1
WO2025131027A1 PCT/CN2024/140840 CN2024140840W WO2025131027A1 WO 2025131027 A1 WO2025131027 A1 WO 2025131027A1 CN 2024140840 W CN2024140840 W CN 2024140840W WO 2025131027 A1 WO2025131027 A1 WO 2025131027A1
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antibody
cancer
seq
amino acid
specific antibody
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Wei Cao
Ying Qin ZANG
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Lanova Medicines Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Cell membrane transporter proteins such as transporters belonging to glucose transporter GLUT, ATP-binding cassette transporter ABC, and solute carrier transporter SLC families are frequently upregulated on cancer cells, compared to adjacent normal cells. High levels of transporters are found in a wide range of solid tumors, correlating with poor survival.
  • One of the potential molecular tumor markers may be the sodium-dependent phosphate transporter NaPi2b encoded by the SLC34A2 (Solute carrier 34 A2) gene.
  • 4-1BB (CD137 and TNFRSF9) , which was first identified as an inducible costimulatory receptor expressed on activated T cells, is a membrane spanning glycoprotein of the Tumor Necrosis Factor (TNF) receptor superfamily.
  • TNF Tumor Necrosis Factor
  • Current understanding of 4-1BB indicates that expression is generally activation dependent and encompasses a broad subset of immune cells including activated NK and NKT cells, regulatory T cells, dendritic cells (DC) including follicular DC; stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, eosinophils, and activated B cells.
  • 4-1BB expression has also been demonstrated on tumor vasculature and atherosclerotic endothelium.
  • the ligand that stimulates 4-1BB (4-1BBL) is expressed on activated antigen-presenting cells (APCs) , myeloid progenitor cells and hematopoeitic stem cells.
  • APCs
  • the cancer cell-specific expression of SLC34A2 and immune cell expression of 4-1BB indicates that these two targets can be a potential cancer target for antibody therapy.
  • the present disclosure provides multi-specific antibodies having binding specificity to the human SLC34A2 protein and 4-1BB protein. These antibodies and fragments are useful in the treatment of diseases and conditions such as cancers.
  • the multi-specific antibody further comprises a Fc domain with reduced or eliminated effector function.
  • the second antibody moiety is a sdAb.
  • One embodiment of the present disclosure provides a multi-specific antibody comprising: (1) a first antibody moiety specifically binds to a human Solute carrier 34 A2 (SLC34A2) protein, and (2) a second antibody moiety specifically binds to a human 4-1BB protein.
  • the multi-specific antibody further comprises a Fc domain.
  • Fc is modified to reduce or eliminate effector function.
  • the second antibody moiety comprises a HCDR1 comprising the amino acid of SSAMS (SEQ ID NO: 34) , a HCDR2 comprising the amino acid of GIYSGGSTYYTESVKD (SEQ ID NO: 35) , and a HCDR3 comprising the amino acid of WGTLRFGVWAEYDH (SEQ ID NO: 36) .
  • the second antibody moiety comprises the amino acid sequence of SEQ ID NO: 9 or a peptide having at least 90%sequence identity to the amino acid sequence of SEQ ID NO: 9.
  • the first antibody moiety comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising heavy chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, comprise amino acid sequences selected from the group consisting of: (a) HCDR1: TNNMH (SEQ ID NO: 10) , HCDR2: AIYPGSGATAYNQKFKG (SEQ ID NO: 11) , HCDR3: GMYGHGAMDY (SEQ ID NO: 12) , LCDR1: KASQDVGTAVA (SEQ ID NO: 13) , LCDR2: WATTRHS (SEQ ID NO: 14) , and LCDR3: QQYSSNPLT (SEQ ID NO: 15) ; (b) HCDR1: SYITH (SEQ ID NO: 16
  • FIG. 3 shows that all the bispecific antibodies bound to SLC34A2 overexpressing HEK293 cells in a concentration-dependent manner.
  • FIG. 5 shows the lead bispecific antibody 30H9-263-1-3-1 exhibited concentration-dependent binding activity to human and cynomolgus 4-1BB while had no cross-reactivity to mouse 4-1BB.
  • FIG. 7 shows that bispecific antibody 30H9-263-1-3-1 efficiently bound to OVCAR3 and HCC4006 with endogenous SLC34A2 expression.
  • FIG. 8 shows that 30H9-263-1-3-1 induced significant 4-1BB activation in the presence of target cells with SLC34A2 expression.
  • FIG. 9 shows that the bispecific antibody 30H9-263-1-3-1 induced significant IL-2 and IFN- ⁇ production by primary PBMCs in the presence of target cells with SLC34A2 expression.
  • FIG. 10 shows that the bispecific antibody 30H9-263-1-3-1 exhibited strong anti-tumor efficacy in human 4-1BB transgenic mice tumor model.
  • a or “an” entity refers to one or more of that entity; for example, “an antibody, ” is understood to represent one or more antibodies.
  • the terms “a” (or “an” ) , “one or more, ” and “at least one” can be used interchangeably herein.
  • polypeptide is intended to encompass a singular “polypeptide” as well as plural “polypeptides, ” and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds) .
  • polypeptide refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product.
  • an equivalent nucleic acid or polynucleotide refers to a nucleic acid having a nucleotide sequence having a certain degree of homology, or sequence identity, with the nucleotide sequence of the nucleic acid or complement thereof.
  • a homolog of a double stranded nucleic acid is intended to include nucleic acids having a nucleotide sequence which has a certain degree of homology with or with the complement thereof. In one aspect, homologs of nucleic acids are capable of hybridizing to the nucleic acid or complement thereof.
  • an equivalent polypeptide refers to a polypeptide having a certain degree of homology, or sequence identity, with the amino acid sequence of a reference polypeptide.
  • the sequence identity is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%.
  • the equivalent polypeptide or polynucleotide has one, two, three, four or five addition, deletion, substitution and their combinations thereof as compared to the reference polypeptide or polynucleotide.
  • the equivalent sequence retains the activity (e.g., epitope-binding) or structure (e.g., salt-bridge) of the reference sequence.
  • CDR complementarity determining region
  • single domain antibodies or “single variable domain (SVD) antibodies” generally refers to antibodies in which a single variable domain (VH or VL) can confer antigen binding. In other words, the single variable domain does not need to interact with another variable domain in order to recognize the target antigen.
  • a “Fab” with regard to an antibody refers to a monovalent antigen-binding fragment of the antibody consisting of a single light chain (both variable and constant regions) bound to the variable region and first constant region of a single heavy chain by a disulfide bond.
  • Fab can be obtained by papain digestion of an antibody at the residues proximal to the N-terminus of the disulfide bond between the heavy chains of the hinge region.
  • a “Fab’ ” refers to a Fab fragment that includes a portion of the hinge region, which can be obtained by pepsin digestion of an antibody at the residues proximal to the C-terminus of the disulfide bond between the heavy chains of the hinge region and thus is different from Fab in a small number of residues (including one or more cysteines) in the hinge region.
  • a “F (ab) 2 ” refers to a dimer of Fab’ that comprises two light chains and part of the two heavy chains.
  • a “single-chain variable fragment” or “scFv” refers to a fusion protein of the variable regions of the heavy (V H ) and light chains (V L ) of immunoglobulins.
  • the regions are connected with a short linker peptide of ten to about 25 amino acids.
  • the linker can be rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the V H with the C-terminus of the V L , or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker.
  • ScFv molecules are known in the art and are described, e.g., in US patent 5,892,019.
  • a full-length antibody comprises two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable domains of the heavy chain and light chain may be referred to as “VH” and “VL” , respectively.
  • the variable regions in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3) .
  • CDRs complementarity determining regions
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ heavy chains, respectively.
  • Several of the major antibody classes are divided into subclasses such as lgG1 ( ⁇ 1 heavy chain) , lgG2 ( ⁇ 2 heavy chain) , lgG3 ( ⁇ 3 heavy chain) , lgG4 ( ⁇ 4 heavy chain) , lgA1 ( ⁇ 1 heavy chain) , or lgA2 ( ⁇ 2 heavy chain) .
  • IgG immunoglobulin molecule
  • a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000.
  • the four chains are typically joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region.
  • Antibodies, antigen-binding polypeptides, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab'and F (ab') 2 , Fd, Fvs, single-chain Fvs (scFv) , single-chain antibodies, disulfide-linked Fvs (sdFv) , fragments comprising either a VK or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to LIGHT antibodies disclosed herein) .
  • anti-Id antigen-binding polypeptides, variants, or derivatives thereof of the disclosure
  • Immunoglobulin or antibody molecules of the disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) , class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • the antigen-binding domain formed by the positioned CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope.
  • the amino acids comprising the CDRs and the framework regions, respectively can be readily identified for any given heavy or light chain variable region by one of ordinary skill in the art, since they have been precisely defined (see “Sequences of Proteins of Immunological Interest, ” Kabat, E., et al., U.S. Department of Health and Human Services, (1983) ; and Chothia and Lesk, J. MoI. Biol., 196: 901-917 (1987) ) .
  • CDR complementarity determining region
  • CDR-H1 begins at approximately amino acid 31 (i.e., approximately 9 residues after the first cysteine residue) , includes approximately 5-7 amino acids, and ends at the next tryptophan residue.
  • CDR-H2 begins at the fifteenth residue after the end of CDR-H1, includes approximately 16-19 amino acids, and ends at the next arginine or lysine residue.
  • CDR-H3 begins at approximately the thirty third amino acid residue after the end of CDR-H2; includes 3-25 amino acids; and ends at the sequence W-G-X-G, where X is any amino acid.
  • CDR-L1 begins at approximately residue 24 (i.e., following a cysteine residue) ; includes approximately 10-17 residues; and ends at the next tryptophan residue.
  • CDR-L2 begins at approximately the sixteenth residue after the end of CDR-L1 and includes approximately 7 residues.
  • CDR-L3 begins at approximately the thirty third residue after the end of CDR-L2 (i.e., following a cysteine residue) ; includes approximately 7-11 residues and ends at the sequence F or W-G-X-G, where X is any amino acid.
  • Antibodies disclosed herein may be from any animal origin including birds and mammals.
  • the antibodies are human, murine, donkey, rabbit, goat, guinea pig, camel, llama, horse, or chicken antibodies.
  • the variable region may be condricthoid in origin (e.g., from sharks) .
  • heavy chain constant region includes amino acid sequences derived from an immunoglobulin heavy chain.
  • a polypeptide comprising a heavy chain constant region comprises at least one of: a CH1 domain, a hinge (e.g., upper, middle, and/or lower hinge region) domain, a CH2 domain, a CH3 domain, or a variant or fragment thereof.
  • an antigen-binding polypeptide for use in the disclosure may comprise a polypeptide chain comprising a CH1 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH2 domain; a polypeptide chain comprising a CH1 domain and a CH3 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH3 domain, or a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, a CH2 domain, and a CH3 domain.
  • a polypeptide of the disclosure comprises a polypeptide chain comprising a CH3 domain.
  • an antibody for use in the disclosure may lack at least a portion of a CH2 domain (e.g., all or part of a CH2 domain) .
  • a CH2 domain e.g., all or part of a CH2 domain
  • the heavy chain constant region may be modified such that they vary in amino acid sequence from the naturally occurring immunoglobulin molecule.
  • a “light chain-heavy chain pair” refers to the collection of a light chain and heavy chain that can form a dimer through a disulfide bond between the CL domain of the light chain and the CH1 domain of the heavy chain.
  • VH domain includes the amino terminal variable domain of an immunoglobulin heavy chain
  • CH1 domain includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain.
  • the CH1 domain is adjacent to the VH domain and is amino terminal to the hinge region of an immunoglobulin heavy chain molecule.
  • Hinge region includes the portion of a heavy chain molecule that joins the CH1 domain to the CH2 domain. This hinge region comprises approximately 25 residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. Hinge regions can be subdivided into three distinct domains: upper, middle, and lower hinge domains (Roux et al., J. Immunol 161: 4083 (1998) ) .
  • chimeric antibody will be held to mean any antibody wherein the immunoreactive region or site is obtained or derived from a first species and the constant region (which may be intact, partial or modified in accordance with the instant disclosure) is obtained from a second species.
  • the target binding region or site will be from a non-human source (e.g. mouse or primate) and the constant region is human.
  • the term "substantially" in the context of a CDR refers to a CDR having the amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%identical to the amino acid sequence of a non-human antibody CDR.
  • a humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F (ab') 2 , Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
  • epitope refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.
  • percent humanization is calculated by determining the number of framework amino acid differences (i.e., non-CDR difference) between the humanized domain and the germline domain, subtracting that number from the total number of amino acids, and then dividing that by the total number of amino acids and multiplying by 100.
  • an antibody By “specifically binds” or “has specificity to, ” it is generally meant that an antibody binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope.
  • the term “specificity” is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope.
  • antibody “A” may be deemed to have a higher specificity for a given epitope than antibody “B, ” or antibody “A” may be said to bind to epitope “C” with a higher specificity than it has for related epitope “D. ”
  • the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of cancer.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable.
  • “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • phrases such as “to a patient in need of treatment” or “a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and/or for treatment.
  • Anti-SLC34A2 Antibody Moiety includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and/or for treatment.
  • antigen-binding moieties that include the heavy chain and light chain variable domains with the CDR regions.
  • the CDRs are summarized in Table A1 below (Kabat numbering) .
  • Table A1 CDR sequences of the anti-SLC34A2 antibody moieties
  • the antibodies and the antigen-binding fragment thereof are humanized and comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 or a peptide having at least 90%, at least 95%, or at least 98%sequence identity to the amino acid sequence of SEQ ID NO: 7.
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine) , acidic side chains (e.g., aspartic acid, glutamic acid) , uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine) , nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan) , beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine
  • a nonessential amino acid residue in an immunoglobulin polypeptide is preferably replaced with another amino acid residue from the same side chain family.
  • a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members.
  • antibodies as disclosed herein may be modified such that they vary in amino acid sequence from the naturally occurring binding polypeptide from which they were derived.
  • a polypeptide or amino acid sequence derived from a designated protein may be similar, e.g., have a certain percent identity to the starting sequence, e.g., it may be 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%identical to the starting sequence.
  • an antibody provided herein is a multispecific antibody, e.g. a bispecific antibody.
  • the term "multispecific antibody” as used herein refers to an antibody comprising an antigen-binding domain that has polyepitopic specificity (i.e., is capable of binding to two, or more, different epitopes on one molecule or is capable of binding to epitopes on two, or more, different molecules) .
  • multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different antigen binding sites (such as a bispecific antibody) .
  • the first antibody domain and the second antibody domain of the multispecific antibody may bind epitopes located within two distinct molecules (intermolecular binding) .
  • a multispecific antibody provided herein may be a bispecific antibody.
  • the term "bispecific antibody” as used herein refers to a multispecific antibody comprising an antibody domain that is capable of binding to two different epitopes on one molecule or is capable of binding to epitopes on two different molecules.
  • a bispecific antibody may also be referred to herein as having “dual specificity” or as being “dual specific. " Exemplary bispecific antibodies may bind both SLC34A2 and any other antigen. In certain embodiments, one of the binding specificities is for SLC34A2 and the other is for 4-1BB. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express SLC34A2.
  • Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983) , WO 93/08829, and Traunecker et al, EMBO J. 10: 3655 (1991) ) , and "knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731,168, WO2009/089004, US2009/0182127, US2011/0287009, Marvin and Zhu, Acta Pharmacol. Sin. (2005) 26 (6) : 649-658, and Kontermann (2005) Acta Pharmacol. Sin., 26: 1-9) .
  • the present disclosure provides the anti-SLC34A2 antigen-binding moieties and the anti-4-1BB antigen-binding moieties as bispecific or multi-specific antibodies.
  • the bispecific antibodies provided herein show comparable binding activity to human SLC34A2 protein and human 4-1BB protein, respectively, as compared with the monospecific anti-SLC34A2 (FIG. 3) and anti-4-1BB antibodies (FIG. 2) , and SLC34A2-dependent 4-1BB signaling (FIG. 4) .
  • the bispecific antibodies provided herein also show specific affinity to monkey 4-1BB protein, but not to mouse 4-1BB protein (FIG. 5) , while exhibiting specific affinity to monkey, rat and mouse SLC34A2 protein (FIG. 6) .
  • the 4-1BB pathway activation (FIG. 8) and T cell activation (FIG. 9) can be induced by targeting the SLC34A2 antigen simultaneously using the bispecific antibodies, which also showed potent in vivo anti-tumor effects (FIG. 10) .
  • the anti-SLC34A2 antibody moiety provided herein has a format of full-length antibody/IgG format, F (ab’) 2 , F (ab) 2 , Fab’, Fab, Fv, scFv or sdAb/VHH/nanobody.
  • the anti-4-1BB antibody moiety provided herein has a format of full-length antibody/IgG format, F (ab’) 2 , F (ab) 2 , Fab’, Fab, Fv, scFv or sdAb/VHH/nanobody.
  • the anti-SLC34A2 antibody moiety provided herein has a Fab’ format and the anti-4-1BB antibody moiety provided herein has a single domain antibody (sdAb) .
  • the bispecific antibody provided herein further comprises a Fc domain.
  • the anti-SLC34A2 antibody moiety is fused to the N-terminus of the Fc domain
  • the anti-4-1BB antibody moiety is fused to the N-terminus of the anti-SLC34A2 antibody moiety.
  • the anti-SLC34A2 antibody moiety is fused to the N-terminus of the Fc domain
  • the anti-4-1BB antibody moiety is fused to the C-terminus of the Fc domain.
  • the Fc region can be engineered to enhance or eliminate effector function.
  • IgG antibodies can induce direct anti-tumor effects by way of indirect anti-tumor effects via the Fc-mediated effector functions that engage other immune cells or killer mechanisms.
  • Effective functions or “antibody effector functions” as used herein refer to biological activities attributable to the binding of Fc region of an antibody to its effectors such as C1 complex and Fc receptor (Fc ⁇ RIIa or Fc ⁇ RIIIa) .
  • the modified IgG1 comprises an N297A modification.
  • the modified IgG1 comprises the amino acid sequence of SEQ ID NO: 37, or a peptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%sequence identity to the amino acid sequence of SEQ ID NO: 37 (Table D) .
  • Table D Sequence of IgG1 N297A Fc domain
  • Linkers within the scope of the present disclosure facilitate functioning of the antibody domains.
  • Linkers within the scope of the present disclosure allow efficient protein processing and export through the bacterial curli secretion machinery as well as provide the proper spatial and physicochemical separation of the respective antibody domains to retain their respective functions.
  • Linkers within the scope of the present disclosure include amino acid residues.
  • the amino acid residues may be any of the naturally occurring amino acid residues.
  • Amino acid residues may also be synthetic amino acids known to those of skill in the art.
  • Representative amino acids which may be used in linkers include Glycine, Alanine, Valine, Leucine, Isoleucine, Serine, Cysteine, Selenocysteine, Threonine, Methionine, Proline, Phenylalanine, Tyrosine, Tryptophan, Histidine, Lysine, Arginine, Aspartate, Glutamate, Asparagine, and Glutamine.
  • the linker length can be any length which may be expressed from a cell, such as a bacterial cell when linking the antibody domains.
  • a linker sequence is a polypeptide sequence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 48 or more amino acids.
  • the antibody comprises the amino acid sequence or one or more moieties not normally associated with an antibody. Exemplary modifications are described in more detail below.
  • an antibody of the disclosure may comprise a flexible linker sequence, or may be modified to add a functional moiety (e.g., PEG, a drug, a toxin, or a label) .
  • the antibodies can be detectably labeled by coupling it to a chemiluminescent compound.
  • the presence of the chemiluminescent-tagged antigen-binding polypeptide is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction.
  • particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.
  • the antibodies can also be detectably labeled using fluorescence emitting metals such as 152 Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA) .
  • DTPA diethylenetriaminepentacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • the present disclosure also provides isolated polynucleotides or nucleic acid molecules encoding the antibodies, variants or derivatives thereof of the disclosure.
  • the polynucleotides of the present disclosure may encode the entire heavy and light chain variable regions of the antigen-binding polypeptides, variants or derivatives thereof on the same polynucleotide molecule or on separate polynucleotide molecules. Additionally, the polynucleotides of the present disclosure may encode portions of the heavy and light chain variable regions of the antigen-binding polypeptides, variants or derivatives thereof on the same polynucleotide molecule or on separate polynucleotide molecules.
  • both the variable and constant regions of the antigen-binding polypeptides of the present disclosure are fully human.
  • Fully human antibodies can be made using techniques described in the art and as described herein. For example, fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Exemplary techniques that can be used to make such antibodies are described in U.S. patents: 6,150,584; 6,458,592; 6,420,140 which are incorporated by reference in their entireties. Treatment Methods
  • the antibodies, variants or derivatives of the present disclosure may be used in certain treatment and diagnostic methods.
  • the present disclosure is further directed to antibody-based therapies which involve administering the antibodies of the disclosure to a patient such as an animal, a mammal, and a human for treating one or more of the disorders or conditions described herein.
  • Therapeutic compounds of the disclosure include, but are not limited to, antibodies of the disclosure (including variants and derivatives thereof as described herein) and nucleic acids or polynucleotides encoding antibodies of the disclosure (including variants and derivatives thereof as described herein) .
  • the antibodies of the disclosure can also be used to treat or inhibit cancer.
  • the cancer cells in the patient express or overexpress SLC34A2.
  • SLC34A2 can be overexpressed in tumor cells, in particular gastric, pancreatic, esophageal, ovarian, and lung tumors. Inhibition of SLC34A2 has been shown to be useful for treating the tumors.
  • the method in one embodiment, entails administering to the patient an effective amount of an antibody of the present disclosure.
  • at least one of the cancer cells (e.g., stromal cells) in the patient over-express SLC34A2.
  • the cell was isolated from the cancer patient him-or her-self. In some embodiments, the cell was provided by a donor or from a cell bank. When the cell is isolated from the cancer patient, undesired immune reactions can be minimized.
  • Non-limiting examples of cancers include bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urethral cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, oesophageal cancer, ovarian cancer, renal cancer, melanoma, prostate cancer and thyroid cancer.
  • Additional diseases or conditions associated with increased cell survival include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia) ) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia) ) , polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease) , multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sar
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the particular antibodies, variant or derivative thereof used, the patient's age, body weight, general health, sex, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. Judgment of such factors by medical caregivers is within the ordinary skill in the art.
  • the amount will also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the compound used, the severity of the disease, and the desired effect. The amount used can be determined by pharmacological and pharmacokinetic principles well known in the art.
  • Methods of administration of the antibodies, variants or include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the antigen-binding polypeptides or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc. ) and may be administered together with other biologically active agents.
  • compositions containing the antigen-binding polypeptides of the disclosure may be administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch) , bucally, or as an oral or nasal spray.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion.
  • Administration can be systemic or local.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
  • the antigen-binding polypeptides or compositions of the disclosure may be administered locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction, with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • care must be taken to use materials to which the protein does not absorb.
  • the amount of the antibodies of the disclosure which will be effective in the treatment, inhibition and prevention of an immune or malignant disease, disorder or condition can be determined by standard clinical techniques.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease, disorder or condition, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the dosage administered to a patient of the antigen-binding polypeptides of the present disclosure is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight, between 0.1 mg/kg and 20 mg/kg of the patient's body weight, or 1 mg/kg to 10 mg/kg of the patient's body weight.
  • human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible.
  • the dosage and frequency of administration of antibodies of the disclosure may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.
  • compositions of the disclosure are administered in combination with cytokines.
  • Cytokines that may be administered with the compositions of the disclosure include, but are not limited to, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, anti-CD40, CD40L, and TNF- ⁇ .
  • compositions of the disclosure are administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.
  • compositions of the disclosure are administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.
  • compositions comprise an effective amount of an antibody, and an acceptable carrier.
  • the composition further includes a second anticancer agent (e.g., an immune checkpoint inhibitor) .
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • a “pharmaceutically acceptable carrier” will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.
  • These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • compositions will contain a therapeutically effective amount of the antigen-binding polypeptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the antibodies of the disclosure can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • Anti-SLC34A2-4-1BB bispecific antibodies were designed in a tetravalent IgG (H) -VHH fusion format, in which the Fc domain was an IgG1 backbone with N297A mutation to disable Fc ⁇ function.
  • the anti-SLC34A2 portion constituted a full IgG unit, while the anti-4-1BB was a VHH placed at the C-terminal side of the Fc fragment via a G4S linker.
  • the format of bispecific antibody is shown in FIG. 1.
  • the sequences of previous identified anti-SLC34A2 arm and anti-4-1BB nanobody used to construct bispecific antibody are shown in Table 1. Table 1.
  • bispecific antibodies were produced transiently in CHO-K1 cells and purified by protein A affinity chromatography.
  • the well qualified bispecific antibodies were applied to in vitro characterization including cell-based 4-1BB binding, SLC34A2 binding and SLC34A2-dependent 4-1BB activation reporter assay.
  • Cell-based 4-1BB binding was applied to in vitro characterization including cell-based 4-1BB binding, SLC34A2 binding and SLC34A2-dependent 4-1BB activation reporter assay.
  • HEK293 cells overexpressing SLC34A2 were incubated with different concentrations of anti-SLC34A2-4-1BB bispecific antibodies at 4 °C for 30 minutes. Then, the cells were washed twice with FACS buffer and stained with PE conjugated secondary antibody at 4 °C for 30 minutes. After wash twice with FACS buffer, MFI of PE was analyzed by a NovoCyte flow cytometer.
  • a reporter gene assay was used.
  • Jurkat cells engineered to have surface 4-1BB expressing and an NF- ⁇ B luciferase reporter construct were used as effector cells.
  • HEK293 cells overexpressing SLC34A2 were used as target cells.
  • effector cells at a density of 1E5 cells per well were co-incubated with 1E4 target cells in the presence of 4-fold serially diluted anti-SLC34A2-4-1BB bispecific antibodies at 37 °C in 5%CO 2 incubator. After overnight incubation, luminescence was obtained by adding the substrate of luciferase and measured by a microplate reader.
  • This example evaluated the binding activity of the lead bispecific antibody of 30H9-263-1-3-1 in Example 1 to SLC34A2 and 4-1BB compared with reference antibodies, using cell-based assays. 3.1 Cell-based binding to 4-1BB
  • the anti-SLC34A2-4-1BB bispecific antibody 30H9-263-1-3-1 was tested for in vitro binding with different species derived 4-1BB expressed on the surface of CHO-K1 cell line with the parental anti-4-1BB antibody 263-1-3-1 as reference.
  • 30H9-263-1-3-1 was analyzed for their binding to different species derived SLC34A2 overexpressed on HEK293 by flow cytometry as described above.
  • the parental SLC34A2 monoclonal antibody 30H9 was included in parallel as reference.
  • all the tested antibodies showed typical sigmoidal binding behavior against engineered HEK293 cells overexpressing human, cynomolgus, rhesus, rat and mouse SLC34A2, while showed no non-specific binding activity to the blank HEK-293 cells.
  • This example used a classical reporter assay to investigate the ability of the anti-SLC34A2-4-1BB bispecific antibody 30H9-263-1-3-1 to activate 4-1BB signaling.
  • the engineered Jurkat cells which stably express 4-1BB and have an NK- ⁇ B luciferase reporter construct integrated into the genome were used as effector cells.
  • HEK-293 cells engineered to overexpress SLC34A2 and tumor cell line OVCAR3 endogenously expressing SLC34A2 were used as target cells.
  • endogenous NF- ⁇ B transcription factors bind to the DNA response elements to induce transcription of the luciferase gene, whose protein product is then quantified by measuring the luminescence signal after adding the substrate.
  • the effector cells and target cells were co-incubated overnight with different concentrations of 30H9-263-1-3-1 or reference antibodies at 37 °C in 5%CO2 incubator. Then, the substrate of luciferase was added, and the luminescence intensity was determined by a microplate reader.
  • the parental anti-4-1BB antibody 263-1-3-1 were used as a control.
  • the bispecific antibody 30H9-263-1-3-1 induced significant 4-1BB activation in the presence of target cells with SLC34A2 expression.
  • the EC50 of 30H9-263-1-3-1 was estimated to be 0.25 nM with human SLC34A2_HEK-293 as target cells and 0.11 nM with OVCAR3 as target cells.
  • 30H9-263-1-3-1 failed to activate 4-1BB signaling in the presence of target cells that did not express SLC34A2, indicating that 30H9-263-1-3-1-mediated 4-1BB activation was dependent on SLC34A2 engagement.
  • the Rhesus SLC34A2 expressing HEK293 engineering cells (HEK293/Rhesus _SLC34A2) were incubated with chimeric Abs (from 200 nM, 4 folds dilution, 8 points) . After incubation at 4°Cfor 60 minutes, the cells were washed with FACS buffer twice, then stained with fluorescent conjugated secondary antibody at 4°C for 30 minutes. After that the cells were washed twice and analyzed by flow cytometry.
  • SLC34A2-dependent primary T cell activation from 200 nM, 4 folds dilution, 8 points
  • human PBMCs (4E5 cells per well) were co-cultured with HEK-293 cells overexpressing SLC34A2 (2E4 cells per well) or OVCAR3 cells in the presence of human anti-CD3 antibody (OKT3 at 0.25 ⁇ g/mL) and serially diluted bispecific antibody.
  • the level of IL-2 in the culture supernatant was determined by Human IL-2 ELISA KIT (CAT#Mabtech-3445-1H-20) after 24 hours incubation. Meanwhile, the level of IFN- ⁇ was determined by Human IFN- ⁇ ELISA KIT (CAT#Mabtech-3420-1H-20) after 48 hours incubation.
  • SLC34A2-4-1BB bispecific antibody induced significant cytokines production by primary PBMCs in the presence of engineered HEK293 cells.
  • the EC 50 for 30H9-263-1-3-1 was estimated to be 0.55 nM for IL-2 and 0.36 nM for IFN- ⁇ . Similar results were observed when PBMCs were co-cultured with OVCAR3 cells.
  • the EC 50 for 30H9-263-1-3-1 in the presence of OVCAR3 was estimated to be 0.24 nM for IL-2 and 0.14 nM for IFN- ⁇ .
  • Example 5 Tumor growth inhibition by Anti-SLC34A2-4-1BB Bispecific Antibody (in vivo)
  • a syngeneic mouse tumor model using human 4-1BB transgenic mice inoculated with MC38 cells ectopically expressing human SLC34A2 was employed.
  • Humanized-4-1BB mice were subcutaneously implanted with 1 ⁇ 10 6 hSLC34A2-MC38 cells.
  • Antibody was given twice a week. Tumor volume was monitored by caliper measurement three times per week for the duration of the experiment.

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Abstract

L'invention concerne des anticorps bispécifiques et multispécifiques qui ciblent un antigène tumoral et 4-1BB, en particulier des anticorps multispécifiques ayant une spécificité de liaison à la protéine SLC34A2 humaine et à la protéine 4-1BB humaine. L'invention concerne également des procédés d'utilisation des anticorps ou des fragments de liaison à l'antigène de ceux-ci pour le traitement du cancer.
PCT/CN2024/140840 2023-12-21 2024-12-20 Anticorps anti-slc34a2/anti-4-1bb et leurs utilisations Pending WO2025131027A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
US20110129483A1 (en) * 2008-01-29 2011-06-02 Gerd Ritter Membrane transporter NaPi2b (SCL34A1) epitope for antibody therapy, antibodies directed thereto, and target for cancer therapy
CN109310885A (zh) * 2016-03-15 2019-02-05 梅尔莎纳医疗公司 NaPi2b靶向抗体-药物缀合物及其使用方法
CN109476747A (zh) * 2016-05-27 2019-03-15 艾伯维生物制药股份有限公司 结合免疫调节性蛋白和肿瘤抗原的双特异性结合蛋白
CN113286825A (zh) * 2018-11-30 2021-08-20 爱必乐生物公司 抗pd-l1/抗4-1bb双特异性抗体及其用途
US20230052369A1 (en) * 2018-10-10 2023-02-16 Zymeworks Inc. Antibody constructs binding 4-1bb and tumor-associated antigens and uses thereof
CN116406380A (zh) * 2020-09-17 2023-07-07 上海霖羲致企业管理有限公司 双特异性重组蛋白及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110129483A1 (en) * 2008-01-29 2011-06-02 Gerd Ritter Membrane transporter NaPi2b (SCL34A1) epitope for antibody therapy, antibodies directed thereto, and target for cancer therapy
CN109310885A (zh) * 2016-03-15 2019-02-05 梅尔莎纳医疗公司 NaPi2b靶向抗体-药物缀合物及其使用方法
CN109476747A (zh) * 2016-05-27 2019-03-15 艾伯维生物制药股份有限公司 结合免疫调节性蛋白和肿瘤抗原的双特异性结合蛋白
US20230052369A1 (en) * 2018-10-10 2023-02-16 Zymeworks Inc. Antibody constructs binding 4-1bb and tumor-associated antigens and uses thereof
CN113286825A (zh) * 2018-11-30 2021-08-20 爱必乐生物公司 抗pd-l1/抗4-1bb双特异性抗体及其用途
CN116406380A (zh) * 2020-09-17 2023-07-07 上海霖羲致企业管理有限公司 双特异性重组蛋白及其用途

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