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CN-121975007-A - AXL antibodies or antigen-binding fragments thereof and uses thereof

CN121975007ACN 121975007 ACN121975007 ACN 121975007ACN-121975007-A

Abstract

The invention belongs to the technical field of antibodies, and particularly relates to an AXL antibody or an antigen binding fragment thereof and application thereof. The antibody or the antigen binding fragment thereof binds with the FNIII-2 domain of the AXL, has better anti-tumor effect compared with the antibody or the antigen binding fragment thereof which binds with other domains of the AXL (such as Ig-1 domain of the AXL), has better affinity to the AXL, and can be used for detecting AXL and AXL related diseases and treating the AXL related diseases.

Inventors

  • ZHANG XUYUAN
  • NIE XIAOHUA
  • YANG ZUMING
  • ZHANG LIGUO

Assignees

  • 中国科学院生物物理研究所

Dates

Publication Date
20260505
Application Date
20241031

Claims (18)

  1. An AXL antibody or antigen-binding fragment thereof that binds to the FNIII-2 domain of AXL.
  2. 2. The AXL antibody or antigen-binding fragment thereof of claim 1, wherein, The antibody or antigen binding fragment thereof comprises: b1 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:51, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having an amino acid sequence as shown in SEQ ID NO. 22, or B2 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:30, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having an amino acid sequence as shown in SEQ ID NO:42, or B3 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:50, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having an amino acid sequence as shown in SEQ ID NO:52, or B4 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:54, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:60, or B5 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:67, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:68, or B6 A heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:69, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:68, or B7 A heavy chain variable region and/or a light chain variable region as described above, wherein said heavy chain variable region and/or light chain variable region comprises a mutation, preferably a conservative substitution, of one or several amino acids compared to the heavy chain variable region and/or light chain variable region described in any of b 1) to b 6).
  3. 3. The AXL antibody or antigen-binding fragment thereof according to any one of claim 1-2, C1 The antibody or antigen binding fragment thereof comprises: a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3; the amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1 and the CDR-L3 are sequentially shown as SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 23 and SEQ ID NO. 24, the amino acid sequence of the CDR-L2 is ATS, and the CDR is defined by an IMGT definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 25, SEQ ID NO. 26 and SEQ ID NO. 24, and the CDR is defined by a Kabat definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 16, SEQ ID NO. 25, SEQ ID NO. 26 and SEQ ID NO. 24, and the CDR is defined by a Chothia definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 27, SEQ ID NO. 28 and SEQ ID NO. 29, and the CDR is defined by a Contact definition scheme, or C2 The antibody or antigen binding fragment thereof comprises: a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3; The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1 and the CDR-L3 are sequentially shown as SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 43 and SEQ ID NO. 44, the amino acid sequence of the CDR-L2 is SAS, and the CDR is defined by an IMGT definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO 34, SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 45, SEQ ID NO 46 and SEQ ID NO 44, and the CDR is defined by a Kabat definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 36, SEQ ID NO 45, SEQ ID NO 46 and SEQ ID NO 44, and the CDR is defined by a Chothia definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 47, SEQ ID NO 48 and SEQ ID NO 49, the CDR is defined by a Contact definition scheme, or C3 The antibody or antigen binding fragment thereof comprises: a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3; the amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1 and the CDR-L3 are sequentially shown as SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 23 and SEQ ID NO. 24, the amino acid sequence of the CDR-L2 is ATS, and the CDR is defined by an IMGT definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 53, SEQ ID NO. 26 and SEQ ID NO. 24, and the CDR is defined by a Kabat definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 16, SEQ ID NO. 53, SEQ ID NO. 26 and SEQ ID NO. 24, and the CDR is defined by a Chothia definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 27, SEQ ID NO. 28 and SEQ ID NO. 29, and the CDR is defined by a Contact definition scheme, or C4 The antibody or antigen binding fragment thereof comprises: a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3; The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1 and the CDR-L3 are sequentially shown as SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 55, SEQ ID NO. 23 and SEQ ID NO. 61, the amino acid sequence of the CDR-L2 is ATY, the CDR is defined by an IMGT definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 56, SEQ ID NO. 15, SEQ ID NO. 57, SEQ ID NO. 62, SEQ ID NO. 63 and SEQ ID NO. 61, and the CDR is defined by a Kabat definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 57, SEQ ID NO. 62, SEQ ID NO. 63 and SEQ ID NO. 61, and the CDR is defined by a Chothia definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are shown as SEQ ID NO 58, SEQ ID NO 20, SEQ ID NO 59, SEQ ID NO 64, SEQ ID NO 65 and SEQ ID NO 66 in sequence, the CDR is defined by a Contact definition scheme, or C5 The antibody or antigen binding fragment thereof comprises: a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3, and A light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3; The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1 and the CDR-L3 are sequentially shown as SEQ ID NO. 70, SEQ ID NO. 71, SEQ ID NO. 72, SEQ ID NO. 23 and SEQ ID NO. 24, the amino acid sequence of the CDR-L2 is ATS, and the CDR is defined by an IMGT definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO 73, SEQ ID NO 74, SEQ ID NO 75, SEQ ID NO 53, SEQ ID NO 26 and SEQ ID NO 24, and the CDR is defined by a Kabat definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are sequentially shown as SEQ ID NO 76, SEQ ID NO 77, SEQ ID NO 75, SEQ ID NO 53, SEQ ID NO 26 and SEQ ID NO 24, and the CDR is defined by a Chothia definition scheme, or The amino acid sequences of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3 are shown as SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29 in sequence, the CDR is defined by a Contact definition scheme, or C6 Heavy chain variable region, and A light chain variable region (light chain variable region), Wherein at least one CDR of said heavy chain variable region and/or light chain variable region comprises a mutation compared to any one of said heavy chain variable region and/or light chain variable region of c 1) to c 5), said mutation being a substitution, deletion or addition of one or several amino acids, preferably said substitution is a conservative substitution.
  4. 4. The AXL antibody or antigen-binding fragment thereof according to claim 1 to 3, d1) The amino acid sequence of the heavy chain variable region comprises: d11 SEQ ID NO. 51, or D12 Amino acid sequence of SEQ ID NO. 51 subjected to substitution, deletion and/or addition of one or several amino acids and having the same function as the protein shown in SEQ ID NO. 51, or D13 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO. 51 and having the same function as the protein shown in SEQ ID NO. 51, and/or The amino acid sequence of the light chain variable region comprises: d14 SEQ ID NO. 22, or D15 Amino acid sequence of SEQ ID NO. 22 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 22, or D16 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 22 and having the same function as the protein shown in SEQ ID NO. 22, or d2) The amino acid sequence of the heavy chain variable region comprises: d21 SEQ ID NO. 30, or D22 Amino acid sequence of SEQ ID NO. 30 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 30, or D23 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO. 30 and having the same function as the protein shown in SEQ ID NO. 30, and/or The amino acid sequence of the light chain variable region comprises: d24 SEQ ID NO. 42, or D25 Amino acid sequence of SEQ ID NO. 42 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 42, or D26 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 42 and having the same function as the protein shown in SEQ ID NO. 42, or d3) The amino acid sequence of the heavy chain variable region comprises: d31 SEQ ID NO. 50, or D32 Amino acid sequence of SEQ ID NO 50 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO 50, or D33 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO 50 and having the same function as the protein shown in SEQ ID NO 50, and/or The amino acid sequence of the light chain variable region comprises: d34 SEQ ID NO. 52, or D35 Amino acid sequence of SEQ ID NO. 52 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 52, or D36 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 52 and having the same function as the protein shown in SEQ ID NO. 52, or d4) The amino acid sequence of the heavy chain variable region comprises: d41 SEQ ID NO. 54, or D42 Amino acid sequence of SEQ ID NO 54 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO 54, or D43 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO. 54 and having the same function as the protein shown in SEQ ID NO. 54, and/or The amino acid sequence of the light chain variable region comprises: d44 SEQ ID NO. 60, or D45 Amino acid sequence of SEQ ID NO 60 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO 60, or D46 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 60 and having the same function as the protein shown in SEQ ID NO. 60, or d5) The amino acid sequence of the heavy chain variable region comprises: d51 SEQ ID NO. 67, or D52 Amino acid sequence of SEQ ID NO 67 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO 67, or D53 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO 67 and having the same function as the protein shown in SEQ ID NO 67, and/or The amino acid sequence of the light chain variable region comprises: d54 SEQ ID NO. 68, or D55 Amino acid sequence of SEQ ID NO. 68 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 68, or D56 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 68 and having the same function as the protein shown in SEQ ID NO. 68, or d6) The amino acid sequence of the heavy chain variable region comprises: d61 SEQ ID NO:69, or D62 Amino acid sequence of SEQ ID NO 69 with one or several amino acid substitutions, deletions and/or additions and with the same function as the protein shown in SEQ ID NO 69, or D63 Amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, or 75% homology to SEQ ID NO 69 and having the same function as the protein shown in SEQ ID NO 69, and/or The amino acid sequence of the light chain variable region comprises: d64 SEQ ID NO. 68, or D65 Amino acid sequence of SEQ ID NO. 68 with one or several amino acid substitutions, deletions and/or additions and having the same function as the protein shown in SEQ ID NO. 68, or D66 An amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% homology to SEQ ID NO. 68 and having the same function as the protein shown in SEQ ID NO. 68.
  5. 5. The AXL antibody or antigen-binding fragment thereof according to claim 1-4, The antibody is IgA, igD, igE, igG or IgM type; Preferably, the antibody is of the IgG type, more preferably of the IgG1, igG2, igG3 or IgG4 type; Preferably, the antigen binding fragment comprises scFv, fab, fab ', (Fab') 2, fv fragment, fd, dsFv; preferably, the antibody is a diabody, a bispecific antibody or a multispecific antibody; Preferably, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and/or a light chain constant region; Preferably, the antibody or antigen binding fragment comprises a murine antibody, a chimeric antibody, a humanized antibody, a fully human antibody.
  6. 6. A biological material associated with the AXL antibody or antigen binding fragment thereof of any one of claims 1-5, said biological material comprising any one of n 1) -n 9): n 1) a nucleic acid molecule encoding the AXL antibody or antigen binding fragment thereof of any one of claims 1-5; n 2) an expression cassette comprising n 1) said nucleic acid molecule; n 3) a vector comprising the nucleic acid molecule of n 1); n 4) a vector comprising the expression cassette of n 2); n 5) a cell comprising the nucleic acid molecule of n 1); n 6) a cell comprising the expression cassette of n 2); n 7) cells comprising n 3) said vector; n 8) cells comprising n 4) said vector; n 9) a cell comprising the AXL antibody or antigen binding fragment thereof of any one of claims 1-5; the cell of any one of n 5) -n 9) does not comprise propagation material.
  7. 7. The biomaterial according to claim 6, wherein the biomaterial, N 3) -n 4) including prokaryotic expression vectors and eukaryotic expression vectors; Preferably, the eukaryotic expression vector comprises a yeast expression vector, a mammalian expression vector, and an insect expression vector.
  8. 8. A conjugate comprising the AXL antibody or antigen-binding fragment thereof according to any one of claims 1-5, and a conjugate moiety selected from at least one of a detectable label, a drug, a toxin, a cytokine, an antibody Fc fragment, an antibody scFv fragment, a radionuclide, an enzyme, a gold nanoparticle/nanorod, a nanomagnetic particle, and a viral coat protein.
  9. 9. The conjugate according to claim 8, wherein the conjugate comprises, The detectable label is a fluorescent or luminescent label; Preferably, the detectable label is selected from any one of acridinium ester, acridine sulfonamide, luminol, isoluminol, horseradish peroxidase and alkaline phosphatase; Preferably, the radionuclide is at least one of a diagnostic isotope and a therapeutic isotope; Preferably, the diagnostic isotope is selected from at least one of Tc-99m, ga-68, F-18, I-123, I-125, I-131, in-111, ga-67, cu-64, zr-89, C-11, lu-177, and Re-188; preferably, the therapeutic isotope is selected from at least one of Lu-177、Y-90、Ac-225、As-211、Bi-212、Bi-213、Cs-137、Cr-51、Co-60、Dy-165、Er-169、Fm-255、Au-198、Ho-166、I-125、I-131、Ir-192、Fe-59、Pb-212、Mo-99、Pd-103、P-32、K-42、Re-186、Re-188、Sm-153、Ra223、Ru-106、Na24、Sr89、Tb-149、Th-227、Xe-133、Yb-169 and Yb-177; preferably, the drug is a cytotoxic drug; Preferably, the cytotoxic drug is selected from at least one of an anti-tubulin drug, a DNA minor groove binding agent, a DNA replication inhibitor, an alkylating agent, an antibiotic, a burnout agent, an anthranilate, a folic acid antagonist, an antimetabolite, a chemosensitizer, a topoisomerase inhibitor, and an antimitotic agent.
  10. 10. An antibody drug conjugate comprising the AXL antibody or antigen-binding fragment thereof of any one of claims 1-5, and a drug covalently linked to said antibody or antigen-binding fragment thereof.
  11. 11. A chimeric antigen receptor comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen-binding domain comprises the AXL antibody or antigen-binding fragment thereof of any one of claims 1-5.
  12. 12. A modified immune cell comprising the chimeric antigen receptor of claim 11.
  13. 13. Use of the AXL antibody or antigen binding fragment thereof of any one of claims 1-5, the biomaterial of any one of claims 6-7, or the conjugate of any one of claims 8-9 in the preparation of a product having any one of functions e 1) -e 2): e1 Detecting the presence or amount of AXL in the sample; e2 Diagnosis or prognosis of AXL-related diseases; preferably, the product comprises at least one of a reagent, a test plate, a chip, a test paper and a kit; preferably, the AXL-related disease comprises a tumor.
  14. 14. A product comprising the AXL antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, or the conjugate according to any one of claims 8 to 9; preferably, the product comprises at least one of a reagent, a test plate, a chip, a test paper and a kit; Preferably, the product has at least one of the functions e 1) -e 2): e1 Detecting the presence or amount of AXL in the sample; e2 Diagnosis or prognosis of AXL-related diseases; preferably, the AXL-related disease comprises a tumor.
  15. 15. Use of the AXL antibody or antigen binding fragment thereof of any one of claims 1-5, the biomaterial of any one of claims 6-7, the conjugate of any one of claims 8-9, the antibody drug conjugate of claim 10, the chimeric antigen receptor of claim 11, or the modified immune cell of claim 12 in the manufacture of a medicament for the treatment and/or prevention of an AXL-related disorder; preferably, the AXL-related disease comprises a tumor.
  16. 16. A pharmaceutical composition comprising the AXL antibody or antigen-binding fragment thereof according to any one of claims 1-5, the biological material according to any one of claims 6-7, the conjugate according to any one of claims 8-9, the antibody drug conjugate according to claim 10, the chimeric antigen receptor according to claim 11, or the modified immune cell according to claim 12.
  17. 17. The pharmaceutical composition of claim 16, wherein, The pharmaceutical composition is used for treating and/or preventing tumors; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition further comprises other active ingredients for controlling tumors; Preferably, the other tumor controlling active ingredient comprises at least one of ifnβ, PD L1 antibodies; preferably, the route of administration of the pharmaceutical composition is parenteral, injectable, oral or topical; preferably, the pharmaceutical composition is in the form of an aqueous solution, suspension, powder, tablet, capsule, granule, injection or infusion.
  18. 18. A method for the preparation of an AXL antibody or antigen binding fragment thereof according to any one of claims 1-5, obtained by culturing a cell according to any one of claims 6-7.

Description

AXL antibodies or antigen-binding fragments thereof and uses thereof Technical Field The invention belongs to the technical field of antibodies, and particularly relates to an AXL antibody or an antigen binding fragment thereof and application thereof. Background AXL is a member of the TAM (TYRO 3/AXL/MER) receptor tyrosine kinase family, belonging to the type I transmembrane protein, with a relative molecular weight of about 140KD in the fully glycosylated state. AXL is divided into extracellular, transmembrane and intracellular 3 portions, wherein the extracellular region comprises two immunoglobulin-like domains (Ig) and two fibronectin III domains (FNIII). Ig region is ligand binding region and FN III region plays a regulatory role in the binding process of AXL and ligand. The intracellular region has tyrosine kinase activity, and after the AXL is combined with ligand-human growth arrest specific protein 6 (GAS 6), phosphorylation occurs, and downstream signal channels are activated, so that biological functions of promoting cell proliferation, resisting apoptosis, promoting migration, invasion and the like are exerted. AXL is highly expressed in various tumor cells, is closely related to poor prognosis of tumors, and is a potential new tumor drug development target. AXL is expressed on host immune cells, including dendritic cells, macrophages, and the like, in addition to tumor cells. AXL, in addition to being able to phagocytose apoptotic cells, can also directly inhibit the activation of Toll-like receptors (TLRs) and the secretion of inflammatory factors in antigen presenting cells. Based on the above mechanism, the AXL is clinically used as a target point for developing the antitumor drug. However, currently developed AXL antibody drugs are mainly directed to competitively binding to AXL Ig-1 domain, inhibiting GAS6-AXL signaling activation, and have mostly validated the direct inhibition of tumors by antibodies in immunodeficiency animal models, without regard to the involvement of the immune system. Therefore, there is a need to develop an AXL antibody or antigen binding fragment thereof that can still effectively exert an antitumor effect in an immune-sound model. Given the high affinity of AXL and GAS6, and the nature of the fact that both generally already bind together, competing directly for GAS6 binding with antibodies has great difficulty in terms of affinity of the antibodies to the receptor, and therefore, it seems more feasible to develop antibodies that do not rely on competition for binding to GAS 6. Disclosure of Invention The object of the first aspect of the invention is to provide AXL antibodies or antigen binding fragments thereof. The object of the second aspect of the invention is to provide a biomaterial related to the AXL antibody or antigen-binding fragment thereof of the first aspect of the invention. The object of a third aspect of the present invention is to provide a conjugate. The fourth aspect of the present invention is directed to an antibody drug conjugate. The object of a fifth aspect of the present invention is to provide a chimeric antigen receptor. The object of the sixth aspect of the present invention is to provide a modified immune cell. The seventh aspect of the present invention is directed to a method for producing the AXL antibody or antigen-binding fragment thereof of the first aspect of the present invention. The object of the eighth aspect of the invention is to provide the use of an AXL antibody or antigen binding fragment thereof of the first aspect of the invention, a biomaterial of the second aspect of the invention, or a conjugate of the third aspect of the invention for the preparation of a product. A ninth aspect of the invention is directed to a product. The tenth aspect of the present invention is directed to the use of an AXL antibody or antigen binding fragment thereof according to the first aspect of the invention, a biomaterial according to the second aspect of the invention, a conjugate according to the third aspect of the invention, an antibody drug conjugate according to the fourth aspect of the invention, a chimeric antigen receptor according to the fifth aspect of the invention, or a modified immune cell according to the sixth aspect of the invention for the manufacture of a medicament for the treatment and/or prophylaxis of an AXL-related disorder. An object of an eleventh aspect of the present invention is to provide a pharmaceutical composition. The object of a twelfth aspect of the present invention is to provide a method for preventing and/or treating AXL-related diseases in a subject. A thirteenth aspect of the invention aims to provide a method. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: In a first aspect of the invention, there is provided an AXL antibody or antigen-binding fragment thereof that binds to the FNIII-2 domain of AXL. In some embodiments, the antibody or ant