Antibodies, nucleic acid, vectors, vector pair, cells, antibody-drug conjugate, pharmaceutical compositions, chimeric antigen receptor and methods of producing an antibody, for treating an individual with cancer, for treating an individual with an eye disease or disorder, for treating an individual with a bone disease or disorder, to decrease the growth rate of a tumor and to kill a tumor cell.

Description

1 / 88 “ANTIBODIES, NUCLEIC ACID, VECTORS, VECTOR PAIR, CELLS, ANTIBODY-DRUG CONJUGATE, PHARMACEUTICAL COMPOSITIONS, CHIMERIC ANTIGEN RECEPTOR AND METHODS OF PRODUCING AN ANTIBODY, OF TREATING AN INDIVIDUAL WITH CANCER, OF TREATING AN INDIVIDUAL WITH AN EYE DISEASE OR DISORDER, OF TREATING AN INDIVIDUAL WITH A BONE DISEASE OR DISORDER, TO DECREASE THE RATE OF TUMOR GROWTH AND TO KILL A CELL "TUMORAL" PRIORITY CLAIM

[001] This request claims priority for PCT / CN2023 / 086082, filed on April 4, 2023, and PCT / CN2023 / 115246, filed on August 28, 2023. The entire content of the above applications is incorporated, by reference, into this document. TECHNICAL FIELD OF THE INVENTION

[002] This disclosure relates to anti-IGF1R (insulin-like growth factor receptor 1) antibodies and their uses. FUNDAMENTALS OF THE INVENTION

[003] Cancer is currently one of the diseases that causes the highest human mortality. According to statistical data from the World Health Organization, in 2012, the global number of cancer incidences and deaths reached 14 million and 8.2 million, respectively. In China, newly diagnosed cancer cases number 3.07 million and the number of deaths is 2.2 million. The recent clinical and commercial success of anticancer antibodies has created great interest in antibody-based therapies.

[004] Furthermore, thyroid eye diseases (TODs), such as thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, continue to be inadequately treated. The Petition 870250090556, dated 03 / 10 / 2025, pages 95 / 204 2 / 88 current therapies, which consist mainly of glucocorticoids, have limited efficacy and present safety problems.

[005] There is a need to develop antibodies for use in various antibody-based therapies to treat cancers, autoimmune diseases, or eye diseases such as thyroid-associated ophthalmopathy. SUMMARY OF THE INVENTION

[006] This disclosure relates to anti-IGF1R antibodies, their antigen-binding fragment and their uses.

[007] In one aspect, the disclosure relates to an antibody, or to the antigen-binding fragment thereof, that binds to insulin-like growth factor receptor 1 (IGF1R) comprising: a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3; in some embodiments, the CDR1 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR1, the CDR2 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR2, and the CDR3 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR3; and a variable light chain (VL) region comprising CDRs 1, 2 and 3;In some embodiments, the CDR1 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected CDR1 of the VL, the CDR2 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected CDR2 of the VL, and the CDR3 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected CDR3 of the VL; in some embodiments, the sequences of; Petition 870250090556, dated 03 / 10 / 2025, pp. 96 / 204 3 / 88 amino acids from selected CDRs 1, 2, and 3 of VH and the amino acid sequences from selected CDRs 1, 2, and 3 of VL are one of the following: (1) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 1, 2 and 3, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 4, 5 and 6, respectively; (2) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 25, 26 and 27, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 4, 5 and 6, respectively; (3) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 7, 8 and 9, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 10, 11 and 12, respectively; (4) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 28, 29 and 30, respectively, and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 10, 11 and 12, respectively; (5) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 13, 14 and 15, respectively, and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 16, 17 and 18, respectively; (6) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 31, 32 and 33, respectively, and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 16, 17 and 18, respectively; (7) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 19, 20 and 21, respectively, Petition 870250090556, dated 03 / 10 / 2025, pp. 97 / 204 4 / 88 and the amino acid sequences of selected VL CDRs 1, 2 and 3 are shown in SEQ ID NOs: 22, 23 and 24, respectively; (8) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 34, 35 and 36, respectively, and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 22, 23 and 24, respectively.

[008] In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 1, 2, and 3, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, according to Kabat's definition. In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 7, 8, and 9, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 10, 11, and 12, respectively, according to Kabat's definition. In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 13, 14, and 15, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 16, 17, and 18, respectively, according to Kabat's definition.In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 19, 20, and 21, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 22, 23, and 24, respectively, according to Kabat's definition. In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 25, 26, and 27, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, according to Chothia's definition. In some... Petition 870250090556, dated 03 / 10 / 2025, pp. 98 / 204 5 / 88 embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 28, 29, and 30, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 10, 11, and 12, respectively, according to the Chothia definition. In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 31, 32, and 33, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 16, 17, and 18, respectively, according to the Chothia definition. In some embodiments, VH comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 34, 35, and 36, respectively, and VL comprises CDRs 1, 2, and 3 with the amino acid sequences shown in SEQ ID NOs: 22, 23, and 24, respectively, according to the Chothia definition.

[009] In some embodiments, the antibody, or antigen-binding fragment, binds specifically to human IGF1R or monkey IGF1R. In some embodiments, the antibody, or antigen-binding fragment, is a human or humanized antibody, or the antigen-binding fragment thereof (e.g., a human IgG1 or IgG4 antibody). In some embodiments, the antibody, or antigen-binding fragment, is a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody).

[0010] In one aspect, the disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in the SEQ ID NOs: Petition 870250090556, dated 03 / 10 / 2025, pp. 99 / 204 6 / 88 1, 2 and 3, respectively, and wherein VH, when paired with a variable light chain (VL) region comprising the amino acid sequence shown in SEQ ID NO: 38, binds to IGF1R; (2) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 4, 5 and 6, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 37, binds to IGF1R; (3) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 25, 26 and 27, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 38, binds to IGF1R; (4) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 7, 8 and 9, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 40, binds to IGF1R; (5) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 39, Petition 870250090556, dated 03 / 10 / 2025, pages 100 / 204 7 / 88 binds to IGF1R; (6) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 28, 29 and 30, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 40, binds to IGF1R; (7) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 13, 14 and 15, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 42, binds to IGF1R; (8) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 41, binds to IGF1R; (9) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 31, 32 and 33, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 42, binds to IGF1R; Petition 870250090556, dated 03 / 10 / 2025, pages 101 / 204 8 / 88 (10) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 19, 20 and 21, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 44, binds to IGF1R; (11) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 43, binds to IGF1R; or (12) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain region (VH) comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 34, 35 and 36, respectively, and wherein the VH, when paired with a variable light chain region (VL) comprising the amino acid sequence presented in SEQ ID NO: 44, binds to IGF1R.

[0011] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 1, 2 and 3, respectively, or SEQ ID NOs: 25, 26 and 27, respectively. In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain, or a fragment of Petition 870250090556, dated 03 / 10 / 2025, pages 102 / 204 9 / 88 same, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 4, 5 and 6, respectively.

[0012] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 7, 8 and 9, respectively, or SEQ ID NOs: 28, 29 and 30, respectively. In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively.

[0013] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 13, 14 and 15, respectively, or SEQ ID NOs: 31, 32 and 33, respectively. In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively.

[0014] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a Petition 870250090556, dated 03 / 10 / 2025, pages 103 / 204 10 / 88 VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 19, 20 and 21, respectively, or SEQ ID NOs: 34, 35 and 36, respectively. In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively.

[0015] In some embodiments, the VH, when paired with a VL, binds specifically to human or monkey IGF1R, or the VL, when paired with a VH, binds specifically to human or monkey IGF1R. In some embodiments, the immunoglobulin heavy chain, or a fragment thereof, is a human or humanized immunoglobulin heavy chain, or a fragment thereof (e.g., a human IgG1 heavy chain or a fragment thereof), and the immunoglobulin light chain, or a fragment thereof, is a human or humanized immunoglobulin light chain or a fragment thereof. In some embodiments, the nucleic acid encodes a single-strand variable fragment (scFv), a multispecific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR). In some embodiments, the nucleic acid is cDNA.

[0016] In one aspect, the disclosure relates to a vector comprising one or more of the nucleic acids described in this document. In one aspect, the disclosure relates to a vector comprising two of the nucleic acids described in this document; in some embodiments, the vector encodes the VH region and the VL region which, together, bind to IGF1R. In one aspect, the disclosure relates to a pair of vectors; in some embodiments, each vector comprises one of the nucleic acids described in this document. Petition 870250090556, dated 03 / 10 / 2025, pp. 104 / 204 11 / 88 document, in some modalities, together, the pair of vectors encodes the VH region and the VL region which together bind to IGF1R.

[0017] In one aspect, the disclosure relates to a cell comprising the vector or vector pair described in this document. In some embodiments, the cell is a CHO cell. In one aspect, the disclosure relates to a cell comprising one or more of the nucleic acids described in this document. In one aspect, the disclosure relates to a cell comprising two of the nucleic acids described in this document. In some embodiments, the two nucleic acids together encode the VH region and the VL region which together bind to IGF1R.

[0018] In one aspect, the disclosure relates to a method of producing an antibody, or an antigen-binding fragment thereof, the method comprising (a) culturing the cell described in this document under conditions sufficient for the cell to produce the antibody or the antigen-binding fragment; and (b) collecting the antibody or the antigen-binding fragment produced by the cell.

[0019] In one aspect, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to IGF1R comprising a variable heavy chain (VH) region comprising an amino acid sequence that is at least 80% identical to a selected VH sequence, and a variable light chain (VL) region comprising an amino acid sequence that is at least 80% identical to a selected VL sequence, in some embodiments, the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 37, and the selected VL sequence is SEQ ID NO: 38; (2) the selected VH sequence is SEQ ID NO: 39, and the selected VL sequence is SEQ ID NO: 40; (3) the selected VH sequence is SEQ ID NO: 41, and the selected VL sequence is SEQ ID NO: 42; and (4) the VH sequence Petition 870250090556, dated 03 / 10 / 2025, pages 105 / 204 The selected 12 / 88 is SEQ ID NO: 43, and the selected VL sequence is SEQ ID NO: 44.

[0020] In some embodiments, VH comprises the sequence with SEQ ID NO: 37 and VL comprises the sequence with SEQ ID NO: 38. In some embodiments, VH comprises the sequence with SEQ ID NO: 39 and VL comprises the sequence with SEQ ID NO: 40. In some embodiments, VH comprises the sequence with SEQ ID NO: 41 and VL comprises the sequence with SEQ ID NO: 42. In some embodiments, VH comprises the sequence with SEQ ID NO: 43 and VL comprises the sequence with SEQ ID NO: 44.

[0021] In some embodiments, the antibody, or antigen-binding fragment, binds specifically to human IGF1R or monkey IGF1R. In some embodiments, the antibody, or antigen-binding fragment, is a human or humanized antibody, or the antigen-binding fragment thereof. In some embodiments, the antibody, or antigen-binding fragment, is a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody).

[0022] In one aspect, the disclosure relates to an antibody, or its antigen-binding fragment, that cross-competes with the antibody, or its antigen-binding fragment, described in this document.

[0023] In one aspect, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to IGF1R comprising a variable heavy chain (VH) region comprising VH CDR1, VH CDR2 and VH CDR3 which are identical to VH CDR1, VH CDR2 and VH CDR3 of a selected VH sequence; and a variable light chain (VL) region comprising VL CDR1, VL CDR2 and VL CDR3 which are identical to VL CDR1, VL CDR2 and VL CDR3 of a selected VL sequence, in some embodiments, the VH sequence Petition 870250090556, dated 03 / 10 / 2025, pages 106 / 204 The selected 13 / 88 and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 37, and the selected VL sequence is SEQ ID NO: 38; (2) the selected VH sequence is SEQ ID NO: 39, and the selected VL sequence is SEQ ID NO: 40; (3) the selected VH sequence is SEQ ID NO: 41, and the selected VL sequence is SEQ ID NO: 42; and (4) the selected VH sequence is SEQ ID NO: 43, and the selected VL sequence is SEQ ID NO: 44.

[0024] In one aspect, the disclosure relates to an antibody-drug conjugate comprising the antibody, or antigen-binding fragment thereof, described herein, covalently linked to a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent.

[0025] In one aspect, the disclosure relates to a method of treating an individual with cancer, the method comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, or the antibody-drug conjugate, described herein, to the individual. In some embodiments, the individual has a solid tumor, brain cancer, lung cancer, melanoma, prostate cancer, esophageal squamous cell carcinoma, leukemia, lymphoma, ovarian cancer, colorectal cancer, head and neck cancer, bladder cancer, kidney cancer, and breast cancer.In some embodiments, the method described in this document additionally comprises the administration of a therapeutically effective amount of an anti-OX40 antibody, an anti-PD1 antibody, an anti-PDL1 antibody, an anti-PDL2 antibody, an anti-LAG-3 antibody, an anti-TIGIT antibody, an anti-CTLA-4 antibody, an anti-GITR antibody, an anti-TIM-3 antibody, an anti-4-1BB antibody and / or an anti-CD40 antibody to the individual.

[0026] In one aspect, disclosure is related to a method Petition 870250090556, dated 03 / 10 / 2025, pages 107 / 204 14 / 88 of reducing the rate of tumor growth, the method comprising contacting a tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof, or the antibody-drug conjugate described in this document.

[0027] In one aspect, the disclosure relates to a method for killing a tumor cell, the method comprising bringing a tumor cell into contact with an effective amount of a composition comprising the antibody or antigen-binding fragment thereof, or the antibody-drug conjugate described in this document.

[0028] In one aspect, the disclosure relates to a method for treating an individual with an eye disease or disorder, the method comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, or the antibody-drug conjugate, described in this document, to the individual.

[0029] In some modalities, the individual has thyroid eye disease (TOD). In some modalities, thyroid eye disease is thyroid-associated ophthalmopathy.

[0030] In one aspect, the disclosure relates to a method for treating an individual with a bone disease or disorder, the method comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, or the antibody-drug conjugate described in this document, to the individual.

[0031] In one aspect, the disclosure relates to a pharmaceutical composition comprising the antibody, or antigen-binding fragment thereof, described herein, and a pharmaceutically acceptable carrier. In one aspect, the disclosure relates to Petition 870250090556, dated 03 / 10 / 2025, pages 108 / 204 15 / 88 a pharmaceutical composition comprising the antibody-drug conjugate described in this document, and a pharmaceutically acceptable carrier.

[0032] In some embodiments, the antibody concentration is about 50 to about 150 mg / mL (for example, about 100 mg / mL).

[0033] In one aspect, the disclosure relates to a chimeric antigen receptor (CAR) comprising the antibody, or antigen-binding fragment thereof, described in this document.

[0034] As used in this document, a “thyroid eye disease (TOD)” is a condition in which the eye muscles, eyelids, tear glands, and fatty tissues behind the eye become inflamed. Symptoms of a thyroid eye disease include, but are not limited to, redness of the eyes and eyelids, swollen, fixed, or bulging eyes.

[0035] As used in this document, the term antibody refers to any antigen-binding molecule that contains at least one (e.g., one, two, three, four, five, or six) complementarity-determining region (CDR) (e.g., any of the three CDRs of an immunoglobulin light chain or any of the three CDRs of an immunoglobulin heavy chain), and is capable of specifically binding to an epitope. Non-limiting examples of antibodies include: monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies, chimeric antibodies, human antibodies, and humanized antibodies. In some embodiments, an antibody may contain an Fc region of a human antibody.The term antibody also includes derivatives, for example, bispecific antibodies, single-chain antibodies, diabodies, linear antibodies, and multispecific antibodies formed from antibody fragments.

[0036] As used in this document, the term antigen-binding fragment refers to a portion of an antibody of length Petition 870250090556, dated 03 / 10 / 2025, pages 109 / 204 16 / 88 total, in which the antibody portion is capable of specifically binding to an antigen. In some embodiments, the antigen-binding fragment contains at least one variable domain (e.g., a variable domain of a heavy chain or a variable domain of a light chain). Non-limiting examples of antibody fragments include, for example, Fab, Fab', F(ab')2, and Fv fragments.

[0037] As used in this document, the term human antibody refers to an antibody that is encoded by an endogenous nucleic acid (e.g., rearranged human immunoglobulin light or heavy chain locus) derived from a human. In some embodiments, a human antibody is collected from a human or produced in a human cell culture (e.g., human hybridoma cells). In some embodiments, a human antibody is produced in a non-human cell (e.g., a mouse or hamster cell line). In some embodiments, a human antibody is produced in a bacterial or yeast cell. In some embodiments, a human antibody is produced in a transgenic non-human animal (e.g., a bovine) containing a non-rearranged or rearranged human immunoglobulin locus (e.g., human immunoglobulin heavy or light chain locus).As used in this document, the term chimeric antibody refers to an antibody that contains a sequence present in at least two different species (e.g., antibodies from two different mammalian species, such as a human antibody and a mouse antibody). A non-limiting example of a chimeric antibody is an antibody containing the variable domain sequences (e.g., all or part of a light chain and / or heavy chain variable domain sequence) of a non-human antibody (e.g., from a mouse) and the constant domains of a human antibody. Additional examples of chimeric antibodies are described in this document and are... Petition 870250090556, dated 03 / 10 / 2025, pages 110 / 204 17 / 88 known in the art.

[0038] As used in this document, the term humanized antibody refers to a non-human antibody that contains a minimal sequence derived from a non-human (e.g., mouse) immunoglobulin and contains sequences derived from a human immunoglobulin. In non-limiting examples, humanized antibodies are human antibodies (recipient antibody) in which residues of the hypervariable region (e.g., CDR) of the recipient antibody are replaced by residues of the hypervariable region (e.g., CDR) of a non-human antibody (e.g., a donor antibody), for example, a mouse, rat, or rabbit antibody, having the desired specificity, affinity, and capability. In some embodiments, the Fv framework residues of the human immunoglobulin are replaced by corresponding non-human (e.g., mouse) immunoglobulin residues.In some embodiments, humanized antibodies may contain residues not found in the recipient antibody or the donor antibody. These modifications can be made to further refine antibody performance. In some embodiments, the humanized antibody contains substantially all of at least one, and typically two, variable domains, in which all, or substantially all, of the hypervariable loops (CDRs) correspond to those of a non-human immunoglobulin (e.g., mouse) and all or substantially all of the structural regions are those of a human immunoglobulin. The humanized antibody may also contain at least a portion of an immunoglobulin constant (Fc) region, typically that of a human immunoglobulin. Humanized antibodies can be produced using molecular biology methods known in the art. Non-limiting examples of methods for generating humanized antibodies are described in this document.

[0039] As used in this document, the term “antibody of Petition 870250090556, dated 03 / 10 / 2025, pp. 111 / 204 "18 / 88 single-chain" refers to a single polypeptide containing at least two immunoglobulin variable domains (e.g., a variable domain of a mammalian immunoglobulin heavy or light chain) that is capable of specifically binding to an antigen. Non-limiting examples of single-chain antibodies are described in this document.

[0040] As used in this document, the terms individual and patient are used interchangeably throughout the descriptive report and describe an animal, human or non-human, to which treatment is provided as defined in the methods of the present invention. Veterinary and non-veterinary applications are contemplated by the present invention. Human patients may be adult humans or juvenile humans (e.g., humans under the age of 18 years). In addition to humans, patients include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, ferrets, cats, dogs, and primates. These include, for example, non-human primates (e.g., monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, swine (e.g., pig, mini-pigs), equines, canines, felines, bovines, and other domestic animals, farm animals, and zoo animals.

[0041] As used in this document, when referring to an antibody, the phrases binds specifically and specific binding mean that the antibody interacts with its target molecule (e.g., IGF1R) preferentially to other molecules because the interaction depends on the presence of a particular structure (i.e., the antigenic determinant or epitope) on the target molecule; in other words, the reagent recognizes and binds to molecules that include a specific structure, and not to all molecules in general. An antibody that binds specifically to the target molecule may be called a target-specific antibody. For example, an antibody that binds specifically to an IGF1R molecule may be called a target-specific antibody. Petition 870250090556, dated 03 / 10 / 2025, p. 112 / 204 19 / 88 specific to IGF1R or an anti-IGF1R antibody.

[0042] As used in this document, the terms “polypeptide”, “peptide” and “protein” are used interchangeably to refer to amino acid polymers of any length of at least two amino acids.

[0043] As used in this document, the terms “polynucleotide”, “nucleic acid molecule” and “nucleic acid sequence” are used interchangeably to refer to polymers of nucleotides of any length of at least two nucleotides and include, without limitation, DNA, RNA, DNA / RNA hybrids and modifications thereof.

[0044] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by one skilled in the art to which this invention pertains. Methods and materials are described in this document for use in the present invention; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned in this document are incorporated by reference in their entirety. In case of conflict, this descriptive report, including the definitions, shall prevail.

[0045] Other features and advantages of the invention will be apparent from the detailed description and figures that follow, and from the claims. DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 shows the internalization of anti-IGF1R antibodies (12A4, 12D1, 10D1 and 10G1). The Teprotumumab analogue was used as a control. Petition 870250090556, dated 03 / 10 / 2025, pp. 113 / 204 20 / 88

[0047] Figure 2A shows the inhibition of IGF1R autophosphorylation by anti-IGF1R antibodies (12A4 and 12D1). The Teprotumumab analogue was used as a control.

[0048] Figure 2B shows the inhibition of IGF1R autophosphorylation by anti-IGF1R antibodies (10D1 and 10G1). The Teprotumumab analogue was used as a control.

[0049] Figure 3 shows the inhibition of IGF-1-induced OPN secretion by anti-IGF1R antibodies (12A4, 12D1, 10D1 and 10G1). The Teprotumumab analog was used as a control.

[0050] Figure 4 shows the pharmacokinetic characteristics of anti-IGF1R antibodies.

[0051] Figure 5 shows the ADCC cytotoxicity of anti-IGF1R antibodies (12A4-YTE and 12D1-QL). The Teprotumumab analogue was used as a positive control.

[0052] Figure 6 shows the levels of IFN-γ cytokine release treated with anti-IGF1R antibodies (12A4-YTE and 12D1-QL). The Teprotumumab analogue was used as a control.

[0053] Figure 7 shows the levels of HA (hyaluronan) release treated with anti-IGF1R antibodies (12A4-YTE and 12D1-QL). The Teprotumumab analogue was used as a control.

[0054] Figure 8 shows the levels of HA (hyaluronan) release treated with anti-IGF1R antibody 12A4-YTE. The Teprotumumab analogue was used as a control. DETAILED DESCRIPTION OF THE INVENTION

[0055] The insulin-like growth factor receptor 1 (IGF1R) is a ubiquitously expressed membrane-bound tyrosine kinase receptor that recognizes its two main ligands, IGF1 and IGF2, and controls several essential cellular functions. IGF activity is highly Petition 870250090556, dated 03 / 10 / 2025, pp. 114 / 204 21 / 88 is relevant in several chronic pulmonary pathologies, including lung cancer. IGF1R signaling has been widely implicated as a critical contributor to the proliferation, survival, migration, and resistance of cancer cells to anticancer therapies. Therefore, targeting IGF signaling is an attractive therapeutic strategy. IGF1R has also been shown to be associated with thyroid eye diseases (TODs) and bone diseases such as osteoporosis and osteosarcoma. Thus, anti-IGF1R antibodies may potentially be used as cancer therapies and in the treatment of other diseases, such as eye or bone diseases.

[0056] This disclosure provides examples of antibodies, antigen-binding fragments thereof, that bind to IGF1R (insulin-like growth factor receptor 1). IGF1R

[0057] IGF1R (insulin-like growth factor receptor 1; UniProt protein database for accession number P08069, IGF1R_HUMAN) is a receptor tyrosine kinase that mediates the actions of insulin-like growth factor 1 (IGF-1). It binds to IGF-1 with high affinity and to IGF-2 and insulin (INS) with lower affinity. Activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and malignant cell survival. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation and tyrosine phosphorylation of multiple substrates, which function as signaling adaptor proteins, including insulin receptor substrates (IRS1 / 2), Shc proteins, and 14-3-3. Phosphorylation of IRS proteins leads to the activation of two main signaling pathways: the PI3K-AKT / PKB pathway and the Ras-MAPK pathway.The activation of the MAPK pathway results in increased cell proliferation, while activation of the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate it. Petition 870250090556, dated 03 / 10 / 2025, pages 115 / 204 22 / 88 the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to the activation of several downstream substrates, including the AKT / PKB protein. AKT phosphorylation, in turn, increases protein synthesis through mTOR activation and triggers the anti-apoptotic effects of IGF1R through phosphorylation and inactivation of BAD. Parallel to PI3K-driven signaling, Grb2 / SOS recruitment by phosphorylated IRS1 or Shc leads to Ras recruitment and activation of the ras-MAPK pathway. In addition to these two main signaling pathways, IGF1R also signals via the Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway. JAK protein phosphorylation can lead to phosphorylation / activation of signal transducer and activator of transcription (STAT) proteins. In particular, STAT3 activation may be essential for the transformative activity of IGF1R. The JAK / STAT pathway activates gene transcription and may be responsible for transformative activity.JNK kinases can also be activated by IGF1R. IGF1 exerts inhibitory activities on JNK activation through phosphorylation and inhibition of MAP3K5 / ASK1, which is capable of directly associating with IGF1R.

[0058] Currently, IGF1R is being evaluated as a pharmacological target in clinical trials for cancer patients, including non-small cell lung cancer (NSCLC). The role that IGF1R plays in the implantation and progression of lung metastases in TME was studied using the Lewis lung carcinoma (LLL) model as a reproducible syngeneic model for NSCLC. The implication of IGF1R as a cancer-promoting factor in TME was studied by analyzing tumor samples from patients with NSCLC and by generating LLL models through heterotopic transplantation or lung metastasis in the context of IGF1R deficiency.

[0059] Thyroid-associated ophthalmopathy, a condition Petition 870250090556, dated 03 / 10 / 2025, pp. 116 / 204 23 / 88 ophthalmopathy, commonly associated with Graves' disease, continues to be inadequately treated. Current therapies, which consist mainly of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor receptor 1 (IGF-IR) may be a novel therapeutic strategy to attenuate the underlying autoimmune pathogenesis of the ophthalmopathy.

[0060] IGF1R has also been found to interact synergistically with TSHR to increase osteopontin (OPN) secretion in bone diseases. Thyroid-stimulating hormone (TSH), also known as thyrotropin, is a hormone that activates TSH receptors (TSHRs) to stimulate thyroid development in the uterus and thyroid cells to stimulate the production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in adults. Thyroid hormones are essential for healthy skeletal development and bone metabolism. Clinical studies have demonstrated that a euthyroid state in adults is important for bone homeostasis. Hyperthyroidism leads to increased bone resorption, which causes bone reduction and reduced mineralization.

[0061] More information related to IGF1R can be found, for example, in Boutin et al., Front. Endocrinol., May 20, 2020 Sec. Thyroid Endocrinology; Girnita et al., Cell Mol Life Sci. 2014;71:240327; Wang et al., Biomed Res Int. 2018;2018:6057589; and Griffiths et al., Nature. 2020;583:615-9; Ullrich et al., EMBO J. 5:2503-2512 (1986); and Kato et al., J. Biol. Chem. 268:2655-2661 (1993); Kellar et al., Biomed Res Int. 2015;2015:621324; Alfaro-Arnedo et al., Oncogene volume 41, pp. 3625-3639, 2022; Smith et al., N Engl J Med. May 4, 2017;376(18):1748-1761; and Barbesino et al., The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue Supplement_1, September 2022, pp. S47-S56; each of which is incorporated herein, by reference, in full. Petition 870250090556, dated 03 / 10 / 2025, pp. 117 / 204 24 / 88 Anti-IGF1R Antibodies and Antigen-Binding Fragments

[0062] The disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to IGF1R (e.g., human IGF1R). The antibodies and antigen-binding fragments described in this document are capable of binding to IGF1R. In some embodiments, these antibodies block the binding of human IGF1R to the IGF1R ligand (e.g., insulin-like growth factor 1, human IGF-1, or insulin-like growth factor 2, human IGF-2). In some embodiments, these antibodies inhibit human IGF-1-induced cell proliferation. In some embodiments, these antibodies block the IGF-1 / IGF1R or IGF-2 / IGF1R signaling pathway. In some embodiments, these antibodies can initiate complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, these antibodies bind to cells expressing IGF1R.

[0063] The disclosure provides, for example, anti-IGF1R 12A4, 12D1, 10D1, 10G1 antibodies, modified antibodies thereof, including, for example, chimeric antibodies, humanized antibodies and human antibodies.

[0064] The CDR sequences for 12A4 antibodies and 12A4-derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 1, 2, and 3, and CDRs of the light chain variable domain, SEQ ID NOs: 4, 5, and 6, as defined by the Kabat definition. CDRs can also be defined by the Chothia system. Under the Chothia definition, the heavy chain variable domain CDR sequences are presented in SEQ ID NOs: 25, 26, and 27, and the light chain variable domain CDR sequences are presented in SEQ ID NOs: 4, 5, and 6.

[0065] The CDR sequences for 12D1 antibodies and 12D1-derived antibodies include CDRs of the variable heavy chain domain, SEQ Petition 870250090556, dated 03 / 10 / 2025, pp. 118 / 204 25 / 88 ID Nos. 7, 8, and 9, and CDRs of the light chain variable domain, SEQ ID Nos. 10, 11, and 12, as defined by Kabat's definition. Under Chothia's definition, the CDR sequences of the heavy chain variable domain are presented in SEQ ID Nos. 28, 29, and 30, and the CDRs of the light chain variable domain are presented in SEQ ID Nos. 10, 11, and 12.

[0066] The CDR sequences for 10D1 antibodies and 10D1-derived antibodies include heavy chain variable domain CDRs, SEQ ID NOs: 13, 14, and 15, and light chain variable domain CDRs, SEQ ID NOs: 16, 17, and 18, as defined by the Kabat definition. Under the Chothia definition, heavy chain variable domain CDR sequences are presented in SEQ ID NOs: 31, 32, and 33, and light chain variable domain CDRs are presented in SEQ ID NOs: 16, 17, and 18.

[0067] The CDR sequences for 10G1 antibodies and 10G1-derived antibodies include CDRs of the heavy chain variable domain, SEQ ID NOs: 19, 20, and 21, and CDRs of the light chain variable domain, SEQ ID NOs: 22, 23, and 24, as defined by the Kabat definition. Under the Chothia definition, the heavy chain variable domain CDR sequences are presented in SEQ ID NOs: 34, 35, and 36, and the light chain variable domain CDRs are presented in SEQ ID NOs: 22, 23, and 24.

[0068] The amino acid sequence for the variable heavy chain region of antibody 12A4 is presented in SEQ ID NO: 37. The amino acid sequence for the variable light chain region of antibody 12A4 is presented in SEQ ID NO: 38.

[0069] The amino acid sequence for the variable heavy chain region of antibody 12D1 is presented in SEQ ID NO: 39. The amino acid sequence for the variable light chain region of antibody 12D1 is presented in SEQ ID NO: 40.

[0070] The amino acid sequence for the variable region of Petition 870250090556, dated 03 / 10 / 2025, pp. 119 / 204 The 26 / 88 heavy chain of antibody 10D1 is shown in SEQ ID NO: 41. The amino acid sequence for the variable region of the light chain of antibody 10D1 is shown in SEQ ID NO: 42.

[0071] The amino acid sequence for the variable heavy chain region of antibody 10G1 is presented in SEQ ID NO: 43. The amino acid sequence for the variable light chain region of antibody 10G1 is presented in SEQ ID NO: 44.

[0072] The amino acid sequence for the variable heavy chain regions and variable light chain regions of the modified antibodies is also provided. In some embodiments, the variable heavy chain region is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 37, 39, 41, or 43. In some embodiments, the variable light chain region is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 38, 40, 42, or 44. The sequence of the variable heavy chain region can be paired with the corresponding variable light chain region sequence, and together they bind to IGF1R.

[0073] In some embodiments, the variable regions are entirely human, for example, derived from human immunoglobulin heavy chain locus sequences (e.g., recombination of human IGHV, IGHD and IGHJ genes) and / or human immunoglobulin kappa chain locus sequences (e.g., recombination of human IGKV and IGKJ genes).

[0074] In addition, in some embodiments, the antibodies or antigen-binding fragments thereof described in this document may also contain one, two or three variable region heavy chain CDRs selected from the group of SEQ ID NOs: 1-3, SEQ ID NOs: 7-9, SEQ ID NOs: 13-15, SEQ ID NOs: 19-21, SEQ ID NOs: 25-27, Petition 870250090556, dated 03 / 10 / 2025, pp. 120 / 204 27 / 88 SEQ ID Nos: 28-30, SEQ ID Nos: 31-33, SEQ ID Nos: 34-36; and / or one, two, or three variable region light chain CDRs selected from the group of SEQ ID Nos: 4-6, SEQ ID Nos: 10-12, SEQ ID Nos: 16-18, and SEQ ID Nos: 22-24.

[0075] In some embodiments, antibodies may have a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2, and 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VH CDR1, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VH CDR2, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VH CDR3.In some embodiments, the antibody may have a variable light chain (VL) region comprising CDRs 1, 2, and 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VL CDR1, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VL CDR2, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to an amino acid sequence of the selected VL CDR3. The amino acid sequences of selected VH CDRs 1, 2, and 3 and the amino acid sequences of selected VL CDRs 1, 2, and 3 are shown in Table 1 (CDRs according to Kabat's definition) and Table 2 (CDRs according to Chothia's definition). Petition 870250090556, dated 03 / 10 / 2025, pages 121 / 204 28 / 88 Tab 1. Sequences of CDR caps for anti-IGFIR protection Ab CDR 1 da VH SE Q ID NO: CDR2 da VH SE Q ID NO: CDR3 da VH SE Q ID NO: CDR1 da VL SE Q ID NO: CDR2 da VL SE Q ID NO: CDR3 da VL SE Q ID NO: 12 DYG 1 EIDWTGGSKLY 2 DRGAVSPKYY 3 RASQGIR 4 AASR 5 LQHNS 6 A4 MS ADSVKG YYGMDV NDLG LQS YPYT 12 DYG 7 GINWNGGSTD 8 DRGAVTRRYY 9 RASQDIR 10 AASR 11 LQHNS 12 D1 MS AASR 17 LQHNS 18 D1 MS YADSVKG YYGMDV NDLG LQS YPYT 10 DYY 19 YISNSGSFTNY 20 DQAPVTSKYY 21 RASQGIR 22 AASR 23 LQHNS 24 G1 MS ADSVKG YYGMDV NDFA LQR YPYT Tab 2. Sequences of CDR Chothia for anti-IGF1R antibodies Ab CDR1 da VH SE Q ID NO CDR2 da VH SE Q ID NO CDR3 da VH SE Q ID NO CDR1 da VL SE Q ID NO CDR2 da VL SE Q ID NO CDR3 da VL SE Q ID NO 12 A4 GFTFA DY 25 DWTG GS 26 DRGAVSPKYYY YGMDV 27 RASQGIR NDLG 4 AASRL QS 5 LQHNSY PYT 6 12 D1 GFTFD DY 28 NWNG GS 29 DRGAVTRRYYY YGMDV 30 RASQDIRN DLG 10 AASRL QS 11 LQHNSY PYT 12 10 D1 GFTFA DY 31 NWNG GS 32 DRGAVSRRYYY YGMDV 33 RASQDIRN DLG 16 AASRL QS 17 LQHNSY PYT 18 10 G1 EFTFS DY 34 SNSG SF 35 DQAPVTSKYYYY GMDV 36 RASQGIR NDFA 22 AASRL QR 23 LQHNSY PYT 24

[0076] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 1 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 2 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 3 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0077] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 7 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 8 with zero, one, or two insertions, deletions, or substitutions of Petition 870250090556, dated 03 / 10 / 2025, pp. 122 / 204 29 / 88 amino acids; SEQ ID NO: 9 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0078] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 13 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 14 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 15 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0079] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 19 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 20 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 21 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0080] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 25 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 26 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 27 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0081] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 28 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 29 with zero, one, or two insertions, deletions, or substitutions of Petition 870250090556, dated 03 / 10 / 2025, pp. 123 / 204 30 / 88 amino acids; SEQ ID NO: 30 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0082] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 31 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 32 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 33 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0083] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable heavy chain domain containing one, two, or three of the CDRs of SEQ ID NO: 34 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 35 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 36 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0084] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable light chain domain containing one, two, or three of the CDRs of SEQ ID NO: 4 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 5 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 6 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0085] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable light chain domain containing one, two, or three of the CDRs of SEQ ID NO: 10 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 11 with zero, one, or two insertions, deletions, or substitutions of Petition 870250090556, dated 03 / 10 / 2025, pp. 124 / 204 31 / 88 amino acids; SEQ ID NO: 12 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0086] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable light chain domain containing one, two, or three of the CDRs of SEQ ID NO: 16 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 17 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 18 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0087] In some embodiments, the antibody or antigen-binding fragment described in this document may contain a variable light chain domain containing one, two, or three of the CDRs of SEQ ID NO: 22 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 23 with zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 24 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0088] Insertions, deletions, and substitutions may be within the CDR sequence or at one or both terminal ends of the CDR sequence. In some embodiments, the CDR is determined based on the Kabat numbering scheme. In some embodiments, the CDR is determined based on the Chothia definition scheme. In some embodiments, the CDR is determined based on a combination of the Kabat and Chothia definition schemes. In some embodiments, the CDR is determined based on the IMGT definition. In some embodiments, the CDR is determined based on the contact definition.

[0089] Disclosure also provides antibodies, or antigen-binding fragments thereof, that bind to IGF1R. The antibodies or antigen-binding fragments thereof contain a variable region of Petition 870250090556, dated 03 / 10 / 2025, pages 125 / 204 32 / 88 heavy chain (HC) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected HC sequence and a variable light chain (LC) region comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected LC sequence. In some modes, the selected VH sequence is SEQ ID NO: 37 and the selected VL sequence is SEQ ID NO: 38. In some modes, the selected VH sequence is SEQ ID NO: 39 and the selected VL sequence is SEQ ID NO: 40. In some modes, the selected VH sequence is SEQ ID NO: 41 and the selected VL sequence is SEQ ID NO: 42. In some modes, the selected VH sequence is SEQ ID NO: 43 and the selected VL sequence is SEQ ID NO: 44.

[0090] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., gaps may be introduced in one or both of a first and second amino acid or nucleic acid sequence for optimal alignment, and non-homologous sequences may be disregarded for comparison purposes). The length of a reference sequence aligned for comparison purposes is at least 80% of the length of the reference sequence, and in some embodiments, it is at least 90%, 95%, or 100%. Then, the amino acid or nucleotide residues at the corresponding amino acid or nucleotide positions are compared. When a position in the first sequence is occupied by the same amino acid or nucleotide residue as the corresponding position in the second sequence, then the molecules are identical at that position.The percentage of identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of... Petition 870250090556, dated 03 / 10 / 2025, pages 126 / 204 33 / 88 gaps and the length of each gap, which need to be introduced for the ideal alignment of the two sequences. For example, sequence comparison and determination of the percentage of identity between two sequences can be performed using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frame offset gap penalty of 5.

[0091] The disclosure also provides nucleic acid comprising a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or an immunoglobulin light chain. The immunoglobulin heavy chain or immunoglobulin light chain comprises CDRs as shown in Table 1 or Table 2, or has the sequences shown in Table 3. When the polypeptides are paired with the corresponding polypeptide (e.g., a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptides bind to IGF1R. Table 3. Sequences of the variable regions of the heavy chain and variable regions of the light chain of anti-IGF1R antibodies and amino acid sequences discussed in the disclosure. Description Amino acid sequence SEQ ID NO: VH of 12A4 EVQLVQSGGGEIRPGGSLRLSCAASGTFFADYGMSWVRQAPGEGLEW VSEIDWTGGSKLYADSVKGRFTISRDNAKNSLFLQMNSLRAEDTALYYCV RDRGAVSPKYYYYGMDVWGQGTTVTVSS 37 VH of 12A4 EIVLTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYA ASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQHNSYPYTFG QGTKLEIK 38 VH of 12D1 QVQLVESGGGVVRPGGSLRLSCAASGTFDDDYGMSWVRQVPGKGLEW VSGINWNGGSTDYADSVKGRFTISREKAKNSLYLQMNSLRAEDTALYYC VRDRGAVTRRYYYYGMDVWGQGTTVTVSS 39 VL of 12D1 DIQMTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQLKPGKAPKRLIYA ASRLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPYTFG QGTKLEIK 40 VH 10D1 QVQLQQSGGGVVRPGGSLRLSCAASGFTFADYGMSWVRQVPGKGLEW VSGINWNGGSTDYADSVKGRFTISRDNAKHSLYLQMNSLRAEDTAFYYC ARDRGAVSRRYYYYGMDVWGLGTTVTVSS 41 VL AIQLTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQLKPGKAPKRLIYAA 42 Petition 870250090556, dated 03 / 10 / 2025, pp. 127 / 204 34 / 88 Descriçã o Sequência de aminoacidos SEQ ID NO: 10D1 SRLQSGVPSGFSGSGSGTETLTISSLQPEDFATYYCLQHNSYPYTFGQ GTKLEIK VH de 10G1 QVQLVESGGGLVKPGGSLRLSCAASEFTFSDYYMSWIRQSPGKGLEWV SYISNSGSFTNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDSAIYYCVR DQAPVTSKYYYYGMDVWGQGTTVTVSS 43 VL de 10G1 EIVLTQSPSSLSASVGDRVTITCRASQGIRNDFAWYQQKPGKAPKRLIYA ASRLQRGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPYTFG QGTKLEIK 44 IGF1R humana MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLE NCTVIEGYLHILLISSKAEDYRSYRPKLTVITEYLLLFRVAGLESLGDLFPNL TVIRGWKLFYNYALVIFEMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTV DWSLILDAVSNNYIVGNKPPKECGDLCPGTMEEKPMCEKTTINNEYNYR CWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCSAPDNDTACVAC RHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHD GECMQECPSGFIRNGSQSMYCEGPCPKVCEEEKKTKTIDSVTSAQM LQGCTIFKGNLLINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFL KNLRLILGEEQLEGNYSFYVLDNQNLQQLWDWDHRNLTIKAGKMYFAFN PKLCVSEIYRMEEVTGTKGRQSKGDINTRNGERASCESDVLHFTSTTS KNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDGQDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSEI LYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQP QDGYLYRHNYCSKDKIPIRKYAADGTIDIEEVTENPKTEVCGGEKGPCCAC PKTEAEKQAEKEEAEYRKFENFLHNSIFVPRPERKRRDVMQVANTTMS SRSRNTTAADTYNITDPEELETEYPFFESRVDNKERTVISNLRPFTLYRIDI HSCNHEAEKLGCSASNFFARTMPAEGADPIGPPVTWEPRPENSIFLKW PEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGNY TARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVI MLYVFHRKRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMS RELGQGSFGMVYEGVAKGVVKDEPETRVAIKTVNEAASMRERIFLNEA SVMKEFNCHHVVRLLGVVSQGQPTLVIMELMTRGDLKSYLRSLRPEMEN NPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARNCMVAEDFTV KIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSF GVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMR MCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLE PENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFDERQ PYAHMNGGRKNERALPLPQSSTC 45 IGF1R de macaco MKSGSGEGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLE NCTVIEGYLHILLICSAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIFEMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTV DWSLILDAVSNNYIVGNKPPKECGDLCPGTMEEKPMCEKTTINNEYNYR CWTTNRCQKMCPSACGKRACTENNECCHPECLGSCSAPDNDTACVAC RHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHD GECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQM LQGCTIFKGNLLINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFL KNLRLILGEEQLEGNYSFYVLDNQNLQQLWDWDHRNLTIKAGKMYFAFN PKLCVSEIYRMEEVTGTKGRQSKGDINTRNNGERASCESDVLHFTSTTT WKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDGQDACGSNSW NMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAK SEILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQ RQPQDGYLYRHNYCSKPTIDEEVGPCCACPKTEAEKQAEKEEAEYRKVF ENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTVADTYNITDLEELE TEYPFFESRVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFA RTMPAEGADDIPGPVTWEPRPENSIFLKWPEPENPNGLILMYEIKYGSQV EDQRECVSRQEYRKYGGAKLNRLNPGNYTARIQATSLSGNGSWTDPVF 46 Petition 870250090556, dated 03 / 10 / 2025, pp. 128 / 204 35 / 88 Description of the amino acid sequence SEQ ID NO: FYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHRKRNNSRLGNGVLY ASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKGV VKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQ GQPTLVIMELMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIAD GMAYLNANKFVHRDLAARNCMVAEDFTVKIGDFGMTRDIYETDYYRKGG KGLLPVRWMSPESLKDGVFTTYSDVWSFGVLWEIATLAEQPYQGLSNE QVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFLEIISSIKD EMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDSASSSSLPLP DRHSGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSS TC INSR humano MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHE LENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKD LFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELC YLATIDWSRILDSVEDNYIVLNKDDNEECGDICPGTAKGKTNCPATVINGQ FVERCWTHSHCQKVCPTICSHGCTAEGLCCHSECLGNCSQPDDPK VACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQ GCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTID SVTSAQELRGCTVINGSLIINIRGGNNLAAELANGLIEEISGYLKIRRSYA LVSLSFFRKLRLIRGETLEIGNYSPYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFS YIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACG SNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSD ERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNIT HYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEY EDSAGECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRPSRKRRSL GDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRH FTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFEN NVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRL RGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFV FLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDE WEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASL RERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSY LRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAAR NCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDG VFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPD NCPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEE NKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYE EHIPYTHMNGGKKNGRILTLPRSNPS 47 VH do Teprotum umabeQVELVESGGGVVQPGRSQRLSCAASGFTFSSYGMHWVRQAPGKGLEW VAIIWFDGSSTYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCA RELGRRYFDLWGRGTLVSVSS 48 VL of Teprotum umabe EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD ASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSKWPPWTF GQGTKVESKR 49 constant region of the light chain RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC 50 constant region of the heavy chain of IgG1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 51 Petition 870250090556, dated 03 / 10 / 2025, pp. 129 / 204 36 / 88 Description Amino acid sequence SEQ ID NO: SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK constant region of the heavy chain of IgG1 with mutations YTE ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 52 constant region of the IgG1 heavy chain with QL mutations ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVLHEALHNHYTQKSLSLSPGK 53 human TSHR MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSL PPSTQTLKLIETHLRTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLTKVYSTDIFFILEI TDNPYMTSIPVNAFQG LC NETLTLKLYNNGFTS VQGYAFNGTKLDAVYLN KNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTW TLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSL RQRKSVNALNSPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEE QEDEIIGFGQELKNPQEETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPC EDIMGYKFLRIVVWFVSLLALLGNVFVLLILLTSHYKLNVPRFLMCNLAFAD FCMGMYLLLIASVDLYTHSEYYNHAIDWQTGPGCNTAGFFTVFASELSVY TLTVITLERWYAITFAMRLDRKIRLRHACAIMVGGWVCCFLLALLPLVGISS YAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCCYVKIYITVRNPQYNP GDKDTKIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSKILLVLFYPL NSCANPFLYAIFTKAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQ VQKVTHDMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQTVL 54

[0092] Anti-IGF1R antibodies and antigen-binding fragments may also be antibody variants (including derivatives and conjugates) of antibodies or antibody fragments and multispecific (e.g., bispecific) antibodies or antibody fragments. Additional antibodies provided in this document are polyclonal, monoclonal, multimeric, multispecific (e.g., bispecific), human antibodies, chimeric antibodies (e.g., human-mouse chimera), single-chain antibodies, intracellularly produced (i.e., intrabody) antibodies, and antigen-binding fragments thereof. Antibodies or antigen-binding fragments thereof may be of any type. Petition 870250090556, dated 03 / 10 / 2025, pages 130 / 204 37 / 88 (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof.

[0093] Antibody fragments are suitable for use in the methods provided, provided they retain the desired affinity and specificity of the full-length antibody. Thus, an antibody fragment that binds to IGF1R will retain the ability to bind to IGF1R. An Fv fragment is an antibody fragment containing a complete antigen recognition and binding site. This region consists of a dimer of a variable heavy chain domain and a light chain domain in strong association, which may be covalent in nature, for example, in scFv. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs or a subset thereof confer antigen-binding specificity to the antibody.However, even a single variable domain (or half of an Fv comprising only three antigen-specific CDRs) can have the ability to recognize and bind the antigen, although generally with a lower affinity than the entire binding site. Single-chain Fv or scFv antibody fragments comprise the VH and VL domains (or regions) of the antibody, where these domains are present in a single polypeptide chain. Generally, the scFv polypeptide additionally comprises a polypeptide linker between the VH and VL domains, which allows the scFv to form the desired structure for antigen binding.

[0094] This disclosure also provides an antibody or antigen-binding fragment thereof that cross-competes with any antibody or antigen-binding fragment as described herein. The cross-competition assay is known in the art and is Petition 870250090556, dated 03 / 10 / 2025, pp. 131 / 204 38 / 88 described, for example, in Moore et al., Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein. Journal of Virology 70.3 (1996): 1863-1872, which is incorporated herein by reference in its entirety. In one aspect, the present disclosure also provides an antibody or antigen-binding fragment of the same that binds to the same epitope or region as any antibody or antigen-binding fragment as described herein. The epitope binning assay is known in the art and is described, for example, in Estep et al. High throughput solution-based measurement of antibody-antigen affinity and epitope binning. MAbs. Vol. 5. No. 2. Taylor & Francis, 2013, which is incorporated herein by reference in its entirety. Antibodies and Antigen-Binding Fragments

[0095] This disclosure provides several antibodies and antigen-binding fragments thereof derived from anti-IGF1R antibodies described in this document. In general, antibodies (also called immunoglobulins) consist of two classes of polypeptide chains, light chains and heavy chains. A non-limiting example of an antibody in this disclosure may be an intact four-chain immunoglobulin antibody comprising two heavy chains and two light chains. The heavy chain of the antibody may be of any isotype, including IgM, IgG, IgE, IgA, or IgD, or subisotype, including IgG1, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgE1, IgE2, etc. The light chain may be a kappa light chain or a lambda light chain. An antibody may comprise two identical copies of a light chain and two identical copies of a heavy chain.The heavy chains, each containing a variable domain (or variable region, Vh) and multiple constant domains (or constant regions), link to each other via disulfide bonds within their constant domains to form the antibody stem. Each of the light chains, each containing a variable domain. Petition 870250090556, dated 03 / 10 / 2025, pp. 132 / 204 39 / 88 (or variable region, Vl) and a constant domain (or constant region), it is linked to a heavy chain by a disulfide bond. The variable region of each light chain is aligned with the variable region of the heavy chain to which it is attached. The variable regions of both the light and heavy chains contain three hypervariable regions embedded between more conserved structural regions (FR).

[0096] These hypervariable regions, known as complementarity-determining regions (CDRs), form loops that comprise the antigen-binding surface of the antibody. The four structural regions largely adopt a beta-sheet conformation, and the CDRs form loops connecting the beta-sheet structure and, in some cases, being part of the beta-sheet structure. The CDRs in each chain are held close together by the structural regions and, with the CDRs of the other chain, contribute to the formation of the antigen-binding region.

[0097] Methods for identifying antibody CDR regions by analyzing the antibody's amino acid sequence are well known, and several definitions of CDRs are commonly used. The Kabat definition is based on sequence variability, and the Chothia definition is based on the location of structural loop regions. These methods and definitions are described, for example, in Martin, Protein sequence and structure analysis of antibody variable domains, Antibody engineering, Springer Berlin Heidelberg, 2001. 422-439; Abhinandan, et al. Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains, Molecular Immunology 45.14 (2008): 3832-3839; Wu, TT and Kabat, EA (1970) J. Exp. Med. 132: 211-250; Martin et al., Methods Enzymol. 203:121-53 (1991); Morea et al., Biophys Chem. 68(1-3):9-16 (Oct. 1997); Morea et al., J Mol Biol. 275(2):269-94 (Jan. 1998); Chothia et al., Nature 342(6252):877-83 (Dec.1989); Ponomarenko and Bourne, BMC Structural Biology 7:64 (2007); each of which is incorporated herein, by reference, in full. Petition 870250090556, dated 03 / 10 / 2025, pp. 133 / 204 40 / 88

[0098] CDRs are important for recognizing an antigen epitope. As used in this document, an “epitope” is the smallest portion of a target molecule capable of specifically binding through the antigen-binding domain of an antibody. The minimum size of an epitope can be about three, four, five, six, or seven amino acids, but these amino acids do not need to be in a consecutive linear sequence of the antigen's primary structure, as the epitope can depend on the antigen's three-dimensional configuration based on the antigen's secondary and tertiary structure.

[0099] In some embodiments, the antibody is an intact immunoglobulin molecule (e.g., IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA). IgG subclasses (IgG1, IgG2, IgG3, and IgG4) are highly conserved, differing in their constant region, particularly in their hinges and upper CH2 domains. IgG subclass sequences and differences are known in the art and are described, for example, in Vidarsson, et al., IgG subclasses and allotypes: from structure to effector functions. Frontiers in Immunology 5 (2014); Irani, et al. Molecular properties of human IgG subclasses and their implications for the design of therapeutic monoclonal antibodies against infectious diseases. Molecular Immunology 67.2 (2015): 171-182; Shakib, Farouk, ed. Human IgG subclasses: molecular analysis of structure, function and regulation. Elsevier, 2016; each of which is incorporated into this document, by reference, in full.

[00100] The antibody may also be an immunoglobulin molecule derived from any species (e.g., human, rodent, mouse, camelid). The antibodies disclosed in this document also include, but are not limited to, polyclonal, monoclonal, monospecific, polyspecific, and chimeric antibodies that include an immunoglobulin-binding domain fused to another polypeptide. The term antigen-binding domain or antigen-binding fragment is a Petition 870250090556, dated 03 / 10 / 2025, pp. 134 / 204 41 / 88 portion of an antibody that retains the specific binding activity of the intact antibody, i.e., any portion of an antibody that is capable of specific binding to an epitope on the target molecule of the intact antibody. Includes, for example, Fab, Fab', F(ab')2 and variants of these fragments. Thus, in some embodiments, an antibody or an antigen-binding fragment thereof may be, for example, an scFv, an Fv, an Fd, a dAb, a bispecific antibody, a bispecific scFv, a diabody, a linear antibody, a single-chain antibody molecule, a multispecific antibody formed from antibody fragments and any polypeptide that includes a binding domain that is an antibody-binding domain or is homologous to it.Non-limiting examples of antigen-binding domains include, for example, the heavy chain and / or light chain CDRs of an intact antibody, the variable regions of the heavy and / or light chain of an intact antibody, full-length heavy or light chains of an intact antibody, or an individual heavy chain or light chain CDR of an intact antibody.

[00101] Antibody fragments suitable for use in the methods described in this document are also provided. The Fab fragment contains a variable and constant domain of the light chain and a variable domain and the first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments comprise a pair of Fab fragments that are generally covalently linked near their carboxyl termini by hinge cysteines between them. Other chemical couplings of antibody fragments are also known in the art.

[00102] Diabodies are small antibody fragments with two antigen-binding sites, whose fragments comprise a VH connected to a VL on the same polypeptide chain (VH and VL). By using a very short linker to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of Petition 870250090556, dated 03 / 10 / 2025, pages 135 / 204 42 / 88 another chain and create two antigen-binding sites.

[00103] Linear antibodies comprise a pair of tandem Fd segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding regions. Linear antibodies can be bispecific or monospecific.

[00104] Antibodies and antibody fragments of the present disclosure may be modified in the Fc region to provide desired effector functions or serum half-life.

[00105] Antibody multimerization can be achieved through natural antibody aggregation or through chemical or recombinant ligation techniques known in the art. For example, some percentage of purified antibody preparations (e.g., purified IgG1 molecules) spontaneously form protein aggregates containing antibody homodimers and other higher-order antibody multimers.

[00106] Alternatively, antibody homodimers can be formed by means of chemical linking techniques known in the art. For example, heterobifunctional crosslinking agents, including but not limited to SMCC (succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate) and SATA (N-succinimidyl S-acetylthioacetate), can be used to form antibody multimers. An exemplary protocol for the formation of antibody homodimers is described in Ghetie et al. (Proc. Natl. Acad. Sci. USA 94: 7509-7514, 1997). Antibody homodimers can be converted into Fab'2 homodimers by pepsin digestion. Another way to form antibody homodimers is through the use of the autophilic peptide T15 described in Zhao et al. (J. Immunol. 25:396-404, 2002).

[00107] In some forms, the antibody Petition 870250090556, dated 03 / 10 / 2025, pp. 136 / 204 43 / 88 multispecific is a bispecific antibody. Bispecific antibodies can be produced by engineering the interface between a pair of antibody molecules to maximize the percentage of heterodimers recovered from recombinant cell culture. For example, the interface may contain at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains of the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created at the interface of the second antibody molecule, replacing the large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism to increase heterodimer yield relative to other undesirable end products such as homodimers.This method is described, for example, in WO 96 / 27011, which is incorporated by reference in its entirety.

[00108] Bispecific antibodies include crosslinked or heteroconjugated antibodies. For example, one of the antibodies in the heteroconjugate may be coupled to avidin and the other to biotin. Heteroconjugated antibodies may also be produced using any convenient crosslinking methods. Suitable crosslinking agents and crosslinking techniques are well known in the art and are disclosed in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

[00109] Any of the antibodies or antigen-binding fragments described in this document may be conjugated to a stabilizing agent (e.g., a molecule that increases the half-life of the antibody or antigen-binding fragment in an individual or in solution). Non-limiting examples of stabilizing molecules include: a polymer (e.g., polyethylene glycol) or a protein (e.g., Petition 870250090556, dated 03 / 10 / 2025, pp. 137 / 204 44 / 88 serum albumin, such as human serum albumin). Conjugation with a stabilizing molecule can increase the half-life or extend the biological activity of an antibody or antigen-binding fragment in vitro (e.g., in tissue culture or when stored as a pharmaceutical composition) or in vivo (e.g., in a human).

[00110] In some embodiments, the antibodies or antigen-binding fragments described in this document may be conjugated to a therapeutic agent. The antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof may bind covalently or non-covalently to a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent.

[00111] In some embodiments, the antigen-binding fragment may form part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of single-chain variable fragments (scFv) as described in this document, fused with transmembrane and CD3-zeta endodomains. In some embodiments, the chimeric antigen receptor also comprises intracellular signaling domains of various costimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor comprises multiple signaling domains, e.g., CD3z-CD28-41BB or CD3z-CD28-OX40, to increase potency. Thus, in one aspect, disclosure additionally provides cells (e.g., T cells) that express the chimeric antigen receptors as described in this document.

[00112] In some embodiments, scFv has one variable heavy chain domain and one variable light chain domain. In some embodiments, scFv has two variable heavy chain domains and two Petition 870250090556, dated 03 / 10 / 2025, pp. 138 / 204 45 / 88 variable light chain domains.

[00113] In some modes, sequences (for example, CDRs or VH / VL sequences) of the antibody or antigen-binding fragment thereof, described in this document, can be used to generate a bispecific antibody targeting IGF1R and an additional antigen (e.g., CD3, PD-1, PD-L1, HER2, or EGFR). Antibody Characteristics

[00114] In some embodiments, the antibodies, or antigen-binding fragments thereof, described in this document, block the binding between IGF1R and IGF1R ligands (e.g., IGF-1, IGF2, or insulin (INS)). Thus, by binding to IGF1R, the antibody inhibits the IGF1R signaling pathway. In some embodiments, the antibody may reduce tumor volume in an animal. In some embodiments, the antibody may inhibit IGF-1-induced cell proliferation. In some embodiments, the antibody may inhibit IGF1R autophosphorylation. In some embodiments, the antibody may inhibit IGF-1-induced OPN secretion.

[00115] In some implementations, the antibody (or its antigen-binding fragments) binds specifically to IGF1R (e.g., human IGF1R or monkey IGF1R) with a dissociation rate (koff) of less than 0.1 s-1, less than 0.01 s-1, less than 0.001 s-1, less than 0.0001 s-1, or less than 0.00001 s-1. In some embodiments, the dissociation rate (koff) is greater than 0.01 s-1, greater than 0.001 s-1, greater than 0.0001 s-1, greater than 0.00001 s-1, or greater than 0.000001 s-1.

[00116] In some modalities, the kinetic association rates (kon) are greater than 1x102 / Ms, greater than 1x103 / Ms, greater than 1x104 / Ms, greater than 1x105 / Ms, or greater than 1x106 / Ms. In some modalities, the kinetic association rates (kon) are less than 1 x105 / Ms, less than 1x106 / Ms, or less than 1x107 / Ms. Petition 870250090556, dated 03 / 10 / 2025, pp. 139 / 204 46 / 88

[00117] Affinities can be deduced from the quotient of the kinetic rate constants (KD=koff / kon). In some modalities, KD is less than 1x10⁶M, less than 1x10⁷M, less than 1x10⁸M, less than 1x10⁹M or less than 1x10⁻¹⁰M. In some modalities, KD is less than 50 nM, 30 nM, 20 nM, 15 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM. In some disciplines, the KD is greater than 1x10'7M, greater than 1x10'8M, greater than 1x10'9M, greater than 1x10'10M, greater than 1x10'11M, or greater than 1x10'12M.

[00118] General techniques for measuring the affinity of an antibody for an antigen include, for example, ELISA, RIA, and surface plasmon resonance (SPR). In some embodiments, the antibody binds to human IGF1R (SEQ ID NO: 45) and / or monkey IGF1R (e.g., SEQ ID NO: 46). In some embodiments, the antibody does not bind to human IGF1R and / or monkey IGF1R. In some embodiments, the antibody does not bind to the human insulin receptor INSR (e.g., SEQ ID NO: 47).

[00119] In some embodiments, the antibody, or antigen-binding fragment thereof, described in this document has a tumor growth inhibition percentage (TGItv%) greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%. In some modalities, the antibody has a percentage of tumor growth inhibition lower than 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The TGI% can be determined, for example, at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the start of treatment, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the start of treatment. As used in this document, the percentage of tumor growth inhibition (TGI%) is calculated using the Petition 870250090556, dated 03 / 10 / 2025, pages 140 / 204 47 / 88 following equation: TGI (%) = [1-(Ti-To) / (Vi-Vo)]x1OO (Eq. 1) Ti is the mean tumor volume in the treatment group on Day i. To is the mean tumor volume in the treatment group on Day zero. Vi is the mean tumor volume in the control group on Day i. Vo is the mean tumor volume in the control group on Day zero.

[00120] In some embodiments, the antibody, or antigen-binding fragment thereof, described in this document, can inhibit IGF-1-induced cell proliferation. In some embodiments, IGF-1-induced cell proliferation is inhibited by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[00121] In some embodiments, the antibody can inhibit IGF1R autophosphorylation. In some embodiments, IGF1R autophosphorylation is inhibited by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[00122] In some embodiments, the antibody can inhibit IGF-1-induced OPN secretion. In some embodiments, IGF-1-induced OPN secretion is inhibited by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[00123] In some embodiments, the antibodies or antigen-binding fragments thereof, as described in this document, are IGF1R antagonists. In some embodiments, the antibodies, or antigen-binding fragments thereof, as described in this document, are IGF1R agonists.

[00124] In some forms, antibodies, or Petition 870250090556, dated 03 / 10 / 2025, pp. 141 / 204 48 / 88 antigen-binding fragments, as described in this document, are non-toxic. In some modalities, no significant differences in body weight can be observed between the treatment group and the control group, for example, at 3 mg / kg.

[00125] In some modalities, antibodies or antigen-binding fragments can induce complement-dependent cytotoxicity (CDC) and / or antibody-dependent cellular cytotoxicity (ADCC) and kill the tumor cell.

[00126] In some embodiments, antibodies or antigen-binding fragments have a functional Fc region. In some embodiments, the effector function of a functional Fc region is antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the effector function of a functional Fc region is phagocytosis. In some embodiments, the effector function of a functional Fc region is ADCC and phagocytosis.

[00127] In some modalities, antibodies or antigen-binding fragments can induce complement-dependent cytotoxicity (CDC).

[00128] In some embodiments, the Fc region is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the antibody is a human IgG1 antibody.

[00129] In some embodiments, antibodies or antigen-binding fragments do not have a functional Fc region. For example, antibodies or antigen-binding fragments are Fab, Fab', F(ab')2, and Fv fragments. In some embodiments, the Fc region has LALA mutations (L234A and L235A mutations in EU numbering) or LALA-PG mutations (L234A, L235A, P329G mutations in EU numbering).

[00130] In some forms, Fc has an SI mutation Petition 870250090556, dated 03 / 10 / 2025, pp. 142 / 204 49 / 88 (S239D and I332E mutations in EU numbering).

[00131] In some forms, Fc has one or more of the following mutations: M252Y / S254T / T256E, according to EU numbering.

[00132] In some forms, the Fc has one or more of the following mutations T250Q / M428L, according to EU numbering.

[00133] In some embodiments, the antibodies or antigen-binding fragments described in this document are stable at high concentrations and / or under stressful storage conditions.

[00134] In some embodiments, the stability of the antibodies or antigen-binding fragments described in this document is measured by the relative amount of potential molecular variants, for example, high molecular weight and / or low molecular weight variants. In some embodiments, the relative amount of potential molecular variants is measured using size exclusion high-performance liquid chromatography (SEC-HPLC). Other methods for measuring antibody stability are known in the art.

[00135] In some embodiments, the potential molecular variant(s) is / are present in approximately 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the total sample measured. In some embodiments, the potential molecular variant(s) is / are not detectable in the sample measured. In some embodiments, the main peak representing stable antibodies is present in approximately 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the total sample measured.

[00136] In some forms, the measurement is performed after approximately 1, 2, 3, 4, 5, 6, or 7 days of storage. In some forms, the measurement is performed after approximately 1, 2, 3, 4, 5, 6, or 7 weeks of storage. In some forms, the measurement is performed after Petition 870250090556, dated 03 / 10 / 2025, pages 143 / 204 50 / 88 approximately 4 weeks of storage.

[00137] In some embodiments, the antibodies or antigen-binding fragments described in this document are stored at approximately 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C or higher.

[00138] In some embodiments, the antibodies or antigen-binding fragments described in this document are stored at a concentration of at least or about 50 mg / mL, at least or about 70 mg / mL, at least or about 100 mg / mL, at least or about 120 mg / mL, at least or about 150 mg / mL or more. In some embodiments, the antibodies or antigen-binding fragments described in this document are stored at a concentration of about 50 mg / mL to about 150 mg / mL, about 70 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 90 mg / mL to about 150 mg / mL, about 80 mg / mL to about 120 mg / mL, or about 90 mg / mL to about 110 mg / mL. Methods for Producing Anti-IGFIR Antibodies

[00139] An isolated fragment of human IGF1R (e.g., extracellular region) can be used as an immunogen to generate antibodies using standard techniques for the preparation of polyclonal and monoclonal antibodies. Polyclonal antibodies can be created in animals by multiple injections (e.g., subcutaneous or intraperitoneal injections) of an antigenic peptide or protein. In some embodiments, the antigenic peptide or protein is injected with at least one adjuvant. In some embodiments, the antigenic peptide or protein can be conjugated to an agent that is immunogenic in the species to be immunized. Animals can be injected with the antigenic peptide or protein more than once (e.g., twice, three times, or four times).

[00140] The polypeptide or full-length protein Petition 870250090556, dated 03 / 10 / 2025, pages 144 / 204 51 / 88 can be used or, alternatively, antigenic peptide fragments thereof can be used as immunogens. The antigenic peptide of a protein comprises at least 8 (e.g., at least 10, 15, 20, or 30) amino acid residues of the IGF1R amino acid sequence, and includes an epitope of the protein such that an antibody produced against the peptide forms a specific immune complex with the protein. As described above, the full-length sequence of human IGF1R is known in the art (SEQ ID NO: 45). The full-length sequence of monkey IGF1R is known in the art (SEQ ID NO: 46). In some embodiments, a His-labeled human IGF1R protein (ACRO Biosystems Inc., Cat. No.: IGRH5229, containing positions 31-932 of SEQ ID NO: 45) is used as an immunogen.

[00141] An immunogen is typically used to prepare antibodies by immunizing a suitable individual (e.g., human or transgenic animal expressing at least one human immunoglobulin locus). An appropriate immunogenic preparation may contain, for example, a recombinantly expressed or chemically synthesized polypeptide (e.g., a fragment of human IGF1R). The preparation may additionally include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent.

[00142] Polyclonal antibodies can be prepared as described above by immunizing a suitable individual with an IGF1R polypeptide, or an antigenic peptide thereof (e.g., part of the IGF1R, such as the extracellular region) as an immunogen. The antibody titer in the immunized individual can be monitored over time by standard techniques, such as with an enzyme-linked immunosorbent assay (ELISA) using the immobilized IGF1R polypeptide or peptide. If desired, antibody molecules can be isolated from mammals (e.g., from blood) and subsequently purified by well-known techniques, such as Petition 870250090556, dated 03 / 10 / 2025, pages 145 / 204 52 / 88 protein A or protein G chromatography to obtain the IgG fraction. At an appropriate time after immunization, for example, when specific antibody titers are highest, antibody-producing cells can be obtained from the individual and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler et al. (Nature 256:495-497, 1975), the human B cell hybridoma technique (Kozbor et al., Immunol. Today 4:72, 1983), the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96, 1985), or triome techniques. The technology for producing hybridomas is well known (see, in general, Current Protocols in Immunology, 1994, Coligan et al. (Eds.), John Wiley & Sons, Inc., New York, NY).Hybridoma cells that produce a monoclonal antibody are detected by screening hybridoma culture supernatants for antibodies that bind to the polypeptide or epitope of interest, for example, using a standard ELISA assay.

[00143] The variants of antibodies or antigen-binding fragments described in this document can be prepared by introducing appropriate nucleotide changes into the DNA encoding a human, humanized, or chimeric antibody, or antigen-binding fragment thereof described in this document, or by peptide synthesis. Such variants include, for example, deletions, insertions, or substitutions of residues in the amino acid sequences that make up the antibody's antigen-binding site or an antigen-binding domain. In a population of such variants, some antibodies or antigen-binding fragments will have a higher affinity for the target protein, for example, IGF1R. Any combination of deletions, insertions, and / or combinations can be made to arrive at an antibody or antigen-binding fragment thereof that has a higher binding affinity for the target. The amino acid changes introduced into the antibody or in Petition 870250090556, dated 03 / 10 / 2025, pp. 146 / 204 53 / 88 antigen-binding fragments can also alter or introduce new post-translational modifications in the antibody or antigen-binding fragment, such as altering (e.g., increasing or decreasing) the number of glycosylation sites, altering the type of glycosylation site (e.g., altering the amino acid sequence so that a different sugar is bound by enzymes present in a cell), or introducing new glycosylation sites.

[00144] The antibodies disclosed in this document may be derived from any animal species, including mammals. Non-limiting examples of native antibodies include antibodies derived from humans, primates (e.g., monkeys and apes), cows, pigs, horses, sheep, camelids (e.g., camels and llamas), chickens, goats, and rodents (e.g., rats, mice, hamsters, and rabbits), including transgenic rodents genetically modified to produce human antibodies.

[00145] Human and humanized antibodies include antibodies possessing variable and constant regions derived from (or possessing the same amino acid sequence as those derived from) human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in CDRs.

[00146] A humanized antibody typically has a human frame (FR) grafted with non-human CDRs. Thus, a humanized antibody has one or more amino acid sequences introduced into it from a non-human source. These non-human amino acid residues are often referred to as import residues, which are typically taken from a variable import domain. Humanization can essentially be achieved, for example, by replacing Petition 870250090556, dated 03 / 10 / 2025, pp. 147 / 204 54 / 88 CDRs or CDR sequences from rodents are replaced by the corresponding sequences of a human antibody. These methods are described, for example, in Jones et al. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321.6069 (1986): 522; Riechmann et al. Reshaping human antibodies for therapy. Nature 332.6162 (1988): 323; Dall'Acqua et al. Antibody humanization by framework shuffling. Methods 36.1 (2005): 43-60; each of which is incorporated herein, by reference, in full. Consequently, humanized antibodies are chimeric antibodies in which substantially less of an intact human V domain has been replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically mouse antibodies in which some CDR residues and some FR residues are replaced by residues from analogous sites in human antibodies.

[00147] The choice of human VH and VL domains to be used in the production of humanized antibodies is very important to reduce immunogenicity. According to the so-called “best fit” method, the sequence of the V domain of a mouse antibody is screened against the entire library of known human domain sequences. Then, the human sequence closest to that of the mouse is accepted as the human FR for the humanized antibody (Sims et al. The blocking function of humanized CD18 antibody without cell destruction. The Journal of Immunology 151.4 (1993): 2296-2308; Chothia, et al., Conical structures for the hypervariable regions of immunoglobulins. Journal of Molecular Biology 196.4 (1987): 901-917).

[00148] It is also important that the antibodies be humanized with high specificity and affinity for the antigen and other favorable biological properties. To achieve this goal, humanized antibodies can be prepared by an analytical process. Petition 870250090556, dated 03 / 10 / 2025, pages 148 / 204 55 / 88 of the parental sequences and several conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and familiar to those skilled in the art. Computer programs exist that illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays allows analysis of the probable role of residues in the functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the receptor and import sequences so that the desired antibody characteristic, such as higher affinity for the target antigen(s), is achieved.

[00149] Typically, amino acid sequence variants of human, humanized, or chimeric anti-IGF1R antibodies will contain an amino acid sequence with at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a sequence present in the light or heavy chain of the original antibody.

[00150] In some embodiments, a mouse (e.g., RenMab mouse) with a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus is used to generate antibodies. The heavy chain immunoglobulin locus is a region on the chromosome that contains genes for antibody heavy chains. The locus may include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (union) genes, and mouse heavy chain constant domain genes. The kappa chain immunoglobulin locus is a region on the chromosome that contains genes encoding antibody light chains (kappa chain). The kappa chain immunoglobulin locus may include, for example, IGKV genes. Petition 870250090556, dated 03 / 10 / 2025, pp. 149 / 204 56 / 88 (variable) human, human IGKJ (spindle) genes and mouse light chain constant domain genes. A detailed description of RenMab mice can be found in PCT / CN2020 / 075698, which is incorporated herein by reference in its entirety. The antibodies generated by the mice have a complete human VH, a complete human VL and mouse constant regions. In some embodiments, the human VH and human VL are linked to human IgG constant regions (e.g., IgG1, IgG2, IgG3 and IgG4).

[00151] In some embodiments, a mouse (e.g., RenLite™ mouse) with a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus is used to generate antibodies. The heavy chain immunoglobulin locus is a region on the chromosome that contains genes for antibody heavy chains. The locus may include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (binding) genes, and mouse heavy chain constant domain genes. The kappa chain immunoglobulin locus is a region on the chromosome that contains genes encoding common light chains. The kappa chain immunoglobulin locus may include, for example, a human IGKV (variable) gene, a human IGKJ (binding) gene, and mouse light chain constant domain genes.A detailed description of RenLite™ mice can be found in PCT / CN2021 / 097652, which is incorporated herein by reference in its entirety.

[00152] Identity or homology with respect to an original sequence is generally the percentage of amino acid residues present in the candidate sequence that are identical to a sequence present in the human, humanized or chimeric anti-IGF1R antibody or fragment, after sequence alignment and the introduction of gaps, if necessary, to Petition 870250090556, dated 03 / 10 / 2025, pp. 150 / 204 57 / 88 to achieve the maximum percentage of sequence identity and without considering any conservative substitutions as part of the sequence identity.

[00153] Further modifications can be made to anti-IGF1R antibodies or antigen-binding fragments. For example, one or more cysteine ​​residues can be introduced into the Fc region, thus allowing the formation of disulfide bonds between chains in that region. The homodimeric antibody thus generated can have any half-life increased in vitro and / or in vivo. Homodimeric antibodies with increased half-life in vitro and / or in vivo can also be prepared using heterobifunctional crosslinkers, as described, for example, in Wolff et al. (Monoclonal antibody homodimers: enhanced antitumor activity in nude mice. Cancer research 53.11 (1993): 2560-2565). Alternatively, an antibody can be designed with double Fc regions.

[00154] In some embodiments, a covalent modification can be made to the anti-IGF1R antibody or to its antigen-binding fragment. These covalent modifications can be made by chemical or enzymatic synthesis, or by enzymatic or chemical cleavage. Other types of covalent modifications of the antibody or antibody fragment are introduced into the molecule by the reaction of targeted amino acid residues of the antibody or fragment with an organic derivatizing agent that is capable of reacting with selected side chains or with the N- or C-terminal residues.

[00155] In some embodiments, antibody variants are provided with a carbohydrate structure that does not have fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such an antibody may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain in Asn297, relative to the sum of all Petition 870250090556, dated 03 / 10 / 2025, pp. 151 / 204 58 / 88 as glycostructures linked to Asn 297 (e.g., complex, hybrid, and high-mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located approximately at position 297 in the Fc region (EU numbering of Fc region residues; or position 314 in Kabat numbering); however, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to small sequence variations in antibodies. Such fucosylation variants may have enhanced ADCC function. In some embodiments, to reduce glycan heterogeneity, the Fc region of the antibody can be further manipulated to replace Asparagine at position 297 with Alanine (N297A).

[00156] In some embodiments, to facilitate production efficiency by avoiding Fab arm exchange, the Fc region of the antibodies was further manipulated to replace serine at position 228 (EU numbering) of IgG4 with proline (S228P). A detailed description of the S228 mutation is given, for example, in Silva et al. The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation. Journal of Biological Chemistry 290.9 (2015): 5462-5469, which is incorporated by reference in full. Recombinant vectors

[00157] This disclosure also provides recombinant vectors (e.g., an expression vector) that include an isolated polynucleotide disclosed in this document (e.g., a polynucleotide encoding a polypeptide disclosed in this document), host cells into which the recombinant vectors are introduced (i.e., so that the host cells contain the polynucleotide and / or a Petition 870250090556, dated 03 / 10 / 2025, pages 152 / 204 59 / 88 vector comprising the polynucleotide) and the production of recombinant antibody polypeptides or fragments thereof by recombinant techniques.

[00158] As used in this document, a vector is any construct capable of delivering one or more polynucleotides of interest to a host cell when the vector is introduced into the host cell. An expression vector is capable of delivering and expressing one or more polynucleotides of interest as an encoded polypeptide in a host cell into which the expression vector has been introduced. Thus, in an expression vector, the polynucleotide of interest is positioned for expression in the vector by being operationally linked to regulatory elements, such as a promoter, enhancer, and / or a poly-A tail, within the vector or in the host cell genome at, or near, or flanking the, integration site of the polynucleotide of interest, so that the polynucleotide of interest is translated in the host cell introduced with the expression vector.

[00159] A vector can be introduced into the host cell by methods known in the art, for example, electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection and infection, and / or transduction (e.g., with recombinant virus). Thus, non-limiting examples of vectors include viral vectors (which can be used to generate recombinant viruses), naked DNA or RNA, plasmids, cosmids, phage vectors, and DNA or RNA expression vectors associated with cationic condensation agents.

[00160] In some implementations, a polynucleotide disclosed in this document (for example, a polynucleotide encoding a polypeptide disclosed in this document) is introduced using a viral expression system (for example, vaccinia or other poxvirus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective) virus competent for replication, or may use a defective virus for replication. Petition 870250090556, dated 03 / 10 / 2025, pages 153 / 204 60 / 88 In the latter case, viral propagation will generally occur only in complementary virus-packaging cells. Suitable systems are disclosed, for example, in Fisher-Hoch et al., 1989, Proc. Natl. Acad. Sci. USA 86:317-321; Flexner et al., 1989, Ann. NY Acad Sci. 569:86-103; Flexner et al., 1990, Vaccine, 8:17-21; US ​​Pat. Nos. 4,603,112, 4,769,330 and 5,017,487; WO 89 / 01973; US Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berkner-Biotechniques, 6:616-627, 1988; Rosenfeld et al., 1991, Science, 252:431-434; Kolls et al., 1994, Proc. Natl. Acad. Sci. USA, 91:215-219; KassEisler et al., 1993, Proc. Natl. Acad. Sci. USA, 90:11498-11502; Guzman et al., 1993, Circulation, 88:2838-2848; and Guzman et al., 1993, Cir. Res., 73:1202-1207. The techniques for incorporating DNA into such expression systems are well known to those skilled in the art. DNA can also be naked, as described, for example, in Ulmer et al., 1993, Science, 259:1745-1749, and Cohen, 1993, Science, 259:1691-1692. The uptake of naked DNA can be increased by coating the DNA in biodegradable beads that are efficiently transported into cells.

[00161] For expression, the DNA insert comprising a polynucleotide encoding an antibody or a polynucleotide encoding a polypeptide disclosed in this document may be operatively ligated to an appropriate promoter (e.g., a heterologous promoter), such as the lambda phage PL promoter, the E. coli lac, trp, and tac promoters, the early and late SV40 promoters, and retroviral LTR promoters, to name a few. Other suitable promoters are known to those skilled in the art. In some embodiments, the promoter is a cytomegalovirus (CMV) promoter. The expression constructs may additionally contain transcription initiation and termination sites and, in the transcript region, a ribosome binding site for translation. The coding portion of the mature transcripts expressed by the constructs may include a Petition 870250090556, dated 03 / 10 / 2025, pages 154 / 204 61 / 88 translation starting at the beginning and a stop codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

[00162] As indicated, expression vectors may include at least one selectable marker. Such markers include dihydrofolate reductase or neomycin resistance for eukaryotic cell culture and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells such as E. coli, Streptomyces, and Salmonella typhimurium cells; fungal cells such as yeast cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, Bowes melanoma, and HK 293 cells; and plant cells. Suitable culture media and conditions for the host cells described in this document are known in the art.

[00163] Non-limiting vectors for use in bacteria include pQE70, pQE60, and pQE-9, available from Qiagen; pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, and pNH46A, available from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, and pRIT5, available from Pharmacia. Non-limiting eukaryotic vectors include pWLNEO, pSV2CAT, pOG44, pXT1, and pSG, available from Stratagene; and pSVK3, pBPV, pMSG, and pSVL, available from Pharmacia. Other suitable vectors will be readily apparent to those skilled in the art.

[00164] Suitable non-limiting bacterial promoters for use include the E. coli lacI and lacZ promoters, the T3 and T7 promoters, the gpt promoter, the lambda PR and PL promoters, and the trp promoter. Suitable eukaryotic promoters include the immediate early CMV promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters, retroviral LTR promoters such as those of Rous sarcoma virus (RSV), and metallothionein promoters such as the metallothionein-I promoter of Petition 870250090556, dated 03 / 10 / 2025, pages 155 / 204 62 / 88 mouse.

[00165] In the yeast Saccharomyces cerevisiae, several vectors containing constitutive or inducible promoters, such as factor alpha, alcohol oxidase and PGH, can be used.

[00166] The introduction of the construct into the host cell can be effected by transfection with calcium phosphate, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. These methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods in Molecular Biology (1986), which is incorporated herein by reference in its entirety.

[00167] The transcription of DNA encoding an antibody of the present disclosure by higher eukaryotes can be enhanced by inserting a sequence of enhancers into the vector. Enhancers are cis-acting DNA elements, generally about 10 to 300 bp long, that act to increase the transcriptional activity of a promoter in a given type of host cell. Examples of enhancers include the SV40 enhancer, which is located on the late side of the origin of replication at base pairs 100 to 270, the cytomegalovirus early promoter enhancer, the polyoma late-side enhancer, and adenovirus enhancers.

[00168] For secretion of the translated protein into the endoplasmic reticulum lumen, the periplasmic space, or the extracellular environment, appropriate secretion signals can be incorporated into the expressed polypeptide. The signals can be endogenous to the polypeptide or they can be heterologous signals.

[00169] The polypeptide (e.g., antibody) can be expressed in a modified form, such as a fusion protein (e.g., a Petition 870250090556, dated 03 / 10 / 2025, pages 156 / 204 63 / 88 GST fusion) or with a histidine tag, and may include not only secretion signals but also additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Furthermore, peptide moieties may be added to the polypeptide to facilitate purification. These regions may be removed before final polypeptide preparation. The addition of peptide moieties to polypeptides to generate secretion or excretion, to improve stability and facilitate purification, among other things, is a familiar and routine technique in the field. Treatment methods

[00170] The antibodies or antigen-binding fragments of this disclosure can be used for various therapeutic purposes.

[00171] In one aspect, disclosure provides methods for treating cancer in an individual, methods for reducing the rate of increase in tumor volume in an individual over time, methods for reducing the risk of developing metastasis, or methods for reducing the risk of developing further metastasis in an individual. In some modalities, treatment may stop, slow, delay, or inhibit the progression of a cancer. In some modalities, treatment may result in a reduction in the number, severity, and / or duration of one or more cancer symptoms in an individual.

[00172] In one aspect, disclosure provides methods for treating an eye disease (e.g., a thyroid eye disease (TOD) or thyroid-associated ophthalmopathy) in an individual, methods for reducing the rate of disease progression in an individual over time, methods for reducing the risk of developing the eye disease in an individual. In some Petition 870250090556, dated 03 / 10 / 2025, pages 157 / 204 In 64 / 88 modalities, treatment can interrupt, slow down, delay, or inhibit the progression of an eye disease. In some modalities, treatment may result in a reduction in the number, severity, and / or duration of one or more symptoms of the eye disease in an individual.

[00173] In some modalities, the methods for treating eye disease described in this document are combined with one or more additional therapies. Examples of therapies include, but are not limited to, eyelid surgery, eye muscle surgery, and orbital decompression surgery.

[00174] In one aspect, disclosure provides methods for treating a bone disease in an individual, methods for reducing the rate of progression of the disease in an individual over time, methods for reducing the risk of developing bone disease in an individual. In some modalities, treatment may stop, slow, delay, or inhibit the progression of a bone disease. In some modalities, treatment may result in a reduction in the number, severity, and / or duration of one or more symptoms of bone disease in an individual.

[00175] In one aspect, disclosure provides methods for treating an IGF1R-related disease in an individual, methods for reducing the rate of disease progression in an individual over time, methods for reducing the risk of developing the disease in an individual. In some modalities, treatment may halt, slow, delay, or inhibit the progression of IGF1R-related disease. In some modalities, treatment may result in a reduction in the number, severity, and / or duration of one or more symptoms of IGF1R-related disease in an individual. As used in this document, IGF1R-related disease is a disease that is caused by or related to the activation of the IGF1R signaling pathway. In some modalities, IGF1R-related disease is a cancer. In some modalities, IGF1R-related disease is an eye disease (for Petition 870250090556, dated 03 / 10 / 2025, pages 158 / 204 65 / 88 for example, a thyroid eye disease (TOD) or thyroid-associated ophthalmopathy). In some modalities, the IGF1R-related disease is a bone disease.

[00176] In one aspect, the disclosure presents methods that include administering a therapeutically effective amount of an antibody, or antigen-binding fragment thereof, disclosed herein to an individual in need (e.g., an individual who has, or has been identified or diagnosed as having, a cancer), for example, lung cancer, non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC). In some embodiments, the individual has a solid tumor or advanced solid tumors.

[00177] In some embodiments, the anti-IGF1R antibody is designed to treat non-small cell lung carcinoma (NSCLC) and / or small cell lung cancer (SCLC).

[00178] In some forms, the cancer is non-small cell lung cancer.

[00179] In some embodiments, the compositions and methods disclosed in this document may be used for the treatment of patients at risk of cancer. Patients with cancer may be identified using various methods known in the art.

[00180] In some respects, the disclosure refers to a method of treating an autoimmune disease or inflammation, the method comprising administering to the individual an effective amount of a composition comprising the antibody, or antigen-binding fragment thereof, as described herein, or the antibody-drug conjugate, as described herein.

[00181] In one aspect, disclosure provides methods for treating, preventing, or reducing the risk of developing disorders associated with a Petition 870250090556, dated 03 / 10 / 2025, pages 159 / 204 66 / 88 abnormal or unwanted immune response, for example, an autoimmune disorder. These autoimmune diseases include, without limitation, Graves' disease. In some modalities, antibodies or antigen-binding fragments can be used to treat inflammation. In some modalities, the anti-IGF1R antibody is designed to treat other diseases or disorders, for example, microbial infection and allergic disorders.

[00182] In some respects, the disclosure refers to a method of inhibiting the immune response in an individual, the method comprising administering to the individual an effective amount of a composition comprising the antibody, or antigen-binding fragment thereof, as described herein, or the antibody-drug conjugate, as described herein. In some embodiments, the individual has an autoimmune disease.

[00183] As used in this document, an effective amount means an amount or dosage sufficient to effect beneficial or desired results, including stopping, delaying, slowing, or inhibiting the progression of a disease, for example, cancer. An effective amount varies depending, for example, on the age and body weight of an individual to whom the antibody, antigen-binding fragment, antibody-encoding polynucleotide, vector comprising the polynucleotide and / or compositions thereof will be administered, the severity of the symptoms, and the route of administration, and therefore administration may be determined individually.

[00184] An effective amount may be administered in one or more administrations. By way of example, an effective amount of an antibody, or of an antigen-binding fragment, is an amount sufficient to improve, stop, stabilize, reverse, inhibit, slow down and / or delay the progression of an autoimmune disease or cancer in a patient. Petition 870250090556, dated 03 / 10 / 2025, pp. 160 / 204 67 / 88 or is a sufficient amount to improve, stop, stabilize, reverse, slow down and / or delay the proliferation of a cell (e.g., a biopsied cell, any of the cancer cells described in this document, or cell line (e.g., a cancer cell line)) in vitro. As understood in the art, an effective amount of an antibody or antigen-binding fragment may vary depending, inter alia, on the patient's history as well as other factors such as the type (and / or dosage) of antibody used.

[00185] Effective amounts and schedules for administering the antibodies, antibody-coding polynucleotides, and / or compositions disclosed in this document can be determined empirically, and making such determinations is within the skill of the art. Those skilled in the art will understand that the dosage to be administered varies depending, for example, on the mammal receiving the antibodies, antibody-coding polynucleotides, and / or compositions disclosed in this document, the route of administration, the particular type of antibodies, antibody-coding polynucleotides, antigen-binding fragments, and / or compositions disclosed in this document used, and other drugs being administered to the mammal.

[00186] A typical daily dosage of an effective amount of an antibody is 1 mg / kg to 10 mg / kg (mg per kg of patient weight).

[00187] In any of the methods described in this document, at least one antibody, antigen-binding fragment thereof, or pharmaceutical composition (for example, any of the antibodies, antigen-binding fragments, or pharmaceutical compositions described in this document) and, optionally, at least one additional therapeutic agent may be administered to the individual. In some embodiments, at least two different antibodies and / or antigen-binding fragments are Petition 870250090556, dated 03 / 10 / 2025, pages 161 / 204 68 / 88 administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody or antigen-binding fragment and at least one additional therapeutic agent are administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody or antigen-binding fragment and at least one additional therapeutic agent are administered in two different compositions (e.g., a liquid composition containing at least one antibody or antigen-binding fragment and a solid oral composition containing at least one additional therapeutic agent). In some embodiments, at least one additional therapeutic agent is administered as a pill, tablet, or capsule. In some embodiments, at least one additional therapeutic agent is administered in a sustained-release oral formulation.

[00188] In some embodiments, one or more additional therapeutic agents may be administered to the individual before or after the administration of at least one antibody, antigen-binding antibody fragment or pharmaceutical composition (for example, any of the antibodies, antigen-binding antibody fragments or pharmaceutical compositions described in this document).In some embodiments, one or more additional therapeutic agents and at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (for example, any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described in this document) are administered to the individual such that there is an overlap in the bioactive period of one or more additional therapeutic agents and at least one antibody or antigen-binding fragment (for example, any of the antibodies or antigen-binding fragments described in this document) in the individual.

[00189] In some modalities, the individual may receive Petition 870250090556, dated 03 / 10 / 2025, pp. 162 / 204 69 / 88 or at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (for example, any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described in this document) for a long period of time. A qualified medical professional may determine the duration of the treatment period using any of the methods described in this document to diagnose or monitor the effectiveness of treatment (for example, observation of at least one symptom of cancer).As described in this document, a qualified medical professional may also alter the identity and number (e.g., increase or decrease) of antibodies or antigen-binding antibody fragments (and / or one or more additional therapeutic agents) administered to the individual and may also adjust (e.g., increase or decrease) the dosage or frequency of administration of at least one antibody or antigen-binding antibody fragment (and / or one or more additional therapeutic agents) to the individual based on an assessment of treatment efficacy (e.g., using any of the methods described in this document and known in the art).

[00190] In some embodiments, one or more additional therapeutic agents may be administered to the individual. In some embodiments, the additional therapeutic agent is an anti-CD3 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-HER2 antibody, or an anti-EGFR antibody. Pharmaceutical Compositions and Routes of Administration

[00191] Pharmaceutical compositions containing at least one (e.g., one, two, three, or four) of the antibodies or antigen-binding fragments described in this document are also provided in this document. Two or more (e.g., two, three, or four) of any of the antibodies or antigen-binding fragments described in this document Petition 870250090556, dated 03 / 10 / 2025, pages 163 / 204 70 / 88 may be present in a pharmaceutical composition in any combination. Pharmaceutical compositions may be formulated in any manner known in the art.

[00192] Pharmaceutical compositions are formulated to be compatible with the intended route of administration (e.g., intravenous, intra-arterial, intramuscular, intradermal, subcutaneous, or intraperitoneal). The compositions may include a sterile diluent (e.g., water or sterile saline solution), a fixed oil, or other synthetic solvents, antibacterial or antifungal agents and the like, antioxidants, such as chelating agents, buffers, and isotonic agents, such as sugars, polyalcohols, or salts, or any combination thereof. Liposomal suspensions may also be used as pharmaceutically acceptable vehicles. The compositions may be formulated and placed in ampoules, disposable syringes, or multi-dose vials. When necessary (as, for example, in injectable formulations), adequate fluidity may be maintained, for example, by the use of a coating such as lecithin or a surfactant.The absorption of the antibody, or of the antigen-binding fragment thereof, can be prolonged by the inclusion of an absorption-delaying agent. Alternatively, controlled release can be achieved through microencapsulated implants and delivery systems, which may include biodegradable and biocompatible polymers.

[00193] Compositions containing one or more of the antibodies or antigen-binding fragments described in this document may be formulated for parenteral administration (e.g., intravenous, intra-arterial, intramuscular, intradermal, subcutaneous, or intraperitoneal) in the form of dosage units (i.e., physically discrete units containing a predetermined amount of active compound for ease of administration and uniformity of dosage). Petition 870250090556, dated 03 / 10 / 2025, pages 164 / 204 71 / 88

[00194] Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic, and manufactured under Good Manufacturing Practices (GMP) conditions. Pharmaceutical compositions may be supplied in unit dose form (i.e., the dosage for a single administration). Pharmaceutical compositions may be formulated using one or more physiologically acceptable vehicles, diluents, excipients, or auxiliaries. The formulation depends on the chosen route of administration. For injection, antibodies may be formulated in aqueous solutions, preferably in physiologically compatible buffers to reduce discomfort at the injection site. The solution may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, antibodies may be in lyophilized form for formulation with a suitable vehicle, e.g., sterile pyrogen-free water, prior to use.

[00195] The toxicity and therapeutic efficacy of compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (e.g., monkeys). For example, the LD50 (the lethal dose for 50% of the population) and the ED50 (the therapeutically effective dose in 50% of the population) can be determined: the therapeutic index being the LD50:ED50 ratio. Agents exhibiting high therapeutic indices are preferred. When an agent exhibits an undesirable side effect, care should be taken to minimize potential harm (i.e., reduce unwanted side effects). Toxicity and therapeutic efficacy can be determined by other standard pharmaceutical procedures.

[00196] Data obtained from cell culture assays and animal studies can be used in formulating an appropriate dosage of any given agent for use in an individual (e.g., a human being). A therapeutically effective amount of one or more (per Petition 870250090556, dated 03 / 10 / 2025, pages 165 / 204 72 / 88 example, one, two, three or four) antibodies or antigen-binding fragments thereof (e.g., any of the antibodies or antibody fragments described in this document) will be an amount that treats the disease (e.g., kills cancer cells) in an individual (e.g., a human individual identified as having cancer) or an individual identified as being at risk of developing the disease (e.g., an individual who has already developed cancer but has now been cured), decreases the severity, frequency and / or duration of one or more symptoms of a disease in an individual (e.g., a human being). The efficacy and dosage of any of the antibodies or antigen-binding fragments described in this document may be determined by a healthcare professional or veterinary professional using methods known in the art, as well as by observation of one or more symptoms of disease in an individual (e.g., a human being).Certain factors can influence the dosage and duration needed to effectively treat an individual (for example, the severity of the disease or disorder, previous treatments, the individual's general health and / or age, and the presence of other diseases).

[00197] Exemplary doses include milligram or microgram amounts of any of the antibodies or antigen-binding fragments described in this document per kilogram of body weight (e.g., about 1 mg / kg to about 10 mg / kg). Although these doses cover a wide range, one skilled in the art will understand that therapeutic agents, including antibodies and their antigen-binding fragments, vary in potency, and effective amounts can be determined by methods known in the art. Typically, relatively low doses are administered initially, and the attending healthcare professional or veterinarian (in the case of therapeutic application) or a researcher (when still working in the development phase) may... Petition 870250090556, dated 03 / 10 / 2025, pages 166 / 204 73 / 88 increase the dose subsequently and gradually until an adequate response is obtained. Furthermore, it is understood that the specific dose level for any particular individual depends on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex and diet of the individual, time of administration, route of administration, excretion rate and half-life of the antibody or antibody fragment in vivo.

[00198] Pharmaceutical compositions may be included in a container, package, or dispenser along with instructions for administration. The disclosure also provides methods for manufacturing antibodies or antigen-binding fragments thereof for various uses as described in this document. EXAMPLES

[00199] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1. Generating anti-IGFIR antibody

[00200] To generate antibodies against human IGF1R, RenMab mice were immunized with His-labeled human IGF1R protein (ACRO Biosystems Inc., Cat. No.: IGR-H5229, containing SEQ ID NO: 45 positions 31932). The antibody immune response was monitored by an antigen-specific immunoassay.

[00201] RenMab mice have a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus. The heavy chain immunoglobulin locus is a region on the chromosome that contains genes for antibody heavy chains. The locus includes IGHV (variable), IGHD (diversity), IGHJ (binding), and constant heavy chain domain genes. The kappa chain immunoglobulin locus is a region on the chromosome that contains genes encoding the Petition 870250090556, dated 03 / 10 / 2025, pages 167 / 204 74 / 88 antibody light chains (kappa chain). The kappa chain immunoglobulin locus includes IGKV (variable), IGKJ (binding) genes and the constant light chain domain. A detailed description of RenMab mice can be found in PCT / CN2020 / 075698, which is incorporated herein by reference in its entirety.

[00202] A total of three immunizations were performed. The immunizations were separated by two weeks. One week after the last immunization, retro-orbital blood was collected, and serum antibody titer was detected by fluorescence-activated cell sorting (FACS). Mice with high titers were selected two weeks later for booster immunizations. His-labeled human IGF1R protein or CHO-S cells expressing human IGF1R protein were used for booster immunizations by intraperitoneal injection and tail vein injection, respectively.

[00203] When a desired immune response was achieved, antigen-specific immune cells were isolated from immunized mice to obtain anti-IGF1R antibodies or to obtain the variable region sequences of the light and heavy chains of anti-IGF1R antibodies. For example, single-cell technology (e.g., using Beacon® Optofluidic System, Berkeley Lights Inc.) was used to track and locate plasma cells secreting antigen-specific monoclonal antibodies, and reverse transcription and PCR sequencing were used to obtain the antibody variable region sequences. The obtained variable region sequences were cloned into a vector containing a sequence encoding the constant region of human IgG1 for antibody expression. The binding activity of the expressed antibody to IGF1R was verified using FACS. Examples of antibodies obtained included: 12A4, 12D1, 10D1, and 10G1. Petition 870250090556, dated 03 / 10 / 2025, pp. 168 / 204 75 / 88

[00204] The CDR 1-3 sequences of the VH and VL of 12A4, 12D1, 10D1, and 10G1 are shown in Table 1 or Table 2, and their VH and VL regions are shown in Table 3.

[00205] The constant region may also include some other mutations. For example, when YTE mutations (M252Y / S254T / T256E according to EU numbering) are introduced into the Fc region of 12A4, the resulting antibody is called 12A4-YTE. When QL mutations (T250Q / M428L according to EU numbering) are introduced into the Fc region of 12A4, the resulting antibody is called 12A4-QL. The sequences of the constant region of the light chain and the constant region of the heavy chain with mutations are shown in SEQ ID NOs: 50-53, respectively. Example 2. Binding activity of anti-IGFIR antibodies

[00206] INSR (insulin receptor) and IGF1R are both members of the receptor tyrosine kinase (RTK) superfamily. The binding activity of anti-IGF1R antibodies to human IGF1R, human INSR, and monkey IGF1R was verified by flow cytometry. In summary, CHO-ShIGF1R cells (expressing human IGF1R (SEQ ID NO: 45)), CHO-SfasIGF1R cells (expressing cynomolgus monkey IGF1R (SEQ ID NO: 46)) and CHOS-hINSR cells (expressing SEQ ID NO: 47) were placed in a 96-well plate with a density of 2*10⁵ cells / well, respectively. Purified anti-IGF1R antibody at a concentration of 20 pg / mL was added to each well and incubated at 4 °C for 30 minutes. Then, after washing with PBS, the cells were incubated with Alexa Fluor® 647 anti-human IgG Fcy secondary antibody (Jackson ImmunoResearch Laboratories, Inc., Cat. No.: 109606-170) at 4 °C for 15 minutes before cytometry analysis. flow. Human IgG1 was used as ISO control.The results are shown in the table below. Petition 870250090556, dated 03 / 10 / 2025, pp. 169 / 204 76 / 88 Table 4 Antibody Cells Percentage of positive cells ISO CHO-S-hIGF1R 0.7% CHO-S-fasIGF1R 0.3% CHO-S-hINSR 0.4% Teprotumumab Analog CHO-S-hIGF1R 45.5% CHO-S-fasIGF1R 73.0% CHO-S-hINSR 1.5% 12A4 CHO-S-hIGF1R 50.3% CHO-S-fasIGF1R 54.4% CHO-S-hINSR 0.4% 12D1 CHO-S-hIGF1R 39.3% CHO-S-fasIGF1R 60.7% CHO-S-hINSR 0.5% 10D1 CHO-S-hIGF1R 36.5% CHO-S-fasIGF1R 64.8% CHO-S-hINSR 1.5% 10G1 CHO-S-hIGF1R 46.4% CHO-S-fasIGF1R 73.9% CHO-S-hINSR 0.7%

[00207] Teprotumumab is a human IgG1 monoclonal antibody that targets IGF1R, developed by Genmab in collaboration with River Vision (currently Horizon Pharma) for the treatment of Graves' orbitopathy and scleroderma. The VH and VL sequences of teprotumumab are shown in SEQ ID NO: 48 and SEQ ID NO: 49, respectively.

[00208] The results showed that all four antibodies 12A4, 12D1, 10D1 and 10G1 exhibited binding activity to human and monkey IGF1R, and none of them showed binding activity to human INSR. Example 3. Binding Affinity of Anti-IGFIR Antibodies

[00209] The affinity of anti-IGF1R antibodies for the protein Human IGF1R labeled with His (hIGF1R-His, ACRO Biosystems Inc., Cat. No.: IGR-H5229) and His-labeled cynomolgus monkey IGF1R protein Petition 870250090556, dated 03 / 10 / 2025, pages 170 / 204 77 / 88 (cIGF1R-His, ACRO Biosystems Inc., Cat. No.: IGR-C5225) was measured using surface plasmon resonance (SPR) using a Biacore™ (Biacore, Inc., Piscataway, NJ) 8K Biosensor equipped with pre-immobilized Protein A sensor chips.

[00210] Purified anti-IGF1R antibodies were captured on the Protein A chip (Series S Sensor Chip Protein A) for detection. 1 μg / mL or 10 μg / mL of purified anti-IGF1R antibodies were loaded at 10 pL / min to bind to a concentration gradient of recombinant hIGF1R-His or cIGF1R-His (400 nM, 200 nM, 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.125 nM). The flow rate was 30 pL / min, and the binding and dissociation times were set at 180 s, 800 s, or 1200 s, respectively. The chip was regenerated after the last injection of each titration with a glycine solution (pH 2.0) at 30 pL / min for 30 seconds.

[00211] Kinetic association rates (kon) and dissociation rates (koff) were obtained simultaneously by fitting the data globally to a 1:1 Langmuir binding model (Karlsson, R. Roos, H. Fagerstam, L. Petersson, B., 1994. Methods Enzymology 6. 99-110) using the Biacore™ 8K 3.0 evaluation software. Affinity values ​​were derived from the quotient of the kinetic rate constants (KD=koff / kon).

[00212] As anyone skilled in the art would understand, the same method, with appropriate adjustments for parameters (e.g., antibody concentration), was performed for each antibody tested. The results for the antibodies tested are summarized in the table below. Table 5 Antibody Protein kon (1 / Ms) koff (1 / s) KD (M) 12A4 hIGF1R-His 2.66E+04 5.69E-06 2.14E-10 cIGF1R-His 1.84E+04 1.05E-05 5.68E-10 12D1 hIGF1R-His 6.12E+03 1.05E-05 1.72E-09 cIGF1R-His 6.45E+03 1.80E-05 2.79E-09 10D1 hIGF1R-His 7.75E+03 1.26E-05 1.63E-09 Petition 870250090556, dated 03 / 10 / 2025, pp. 171 / 204 78 / 88 Antibody Protein kon (1 / Ms) koff (1 / s) KD (M) cIGF1R-His 8.36E+03 1.75E-05 2.10E-09 10G1 hIGF1R-His 4.07E+04 1.62E-04 3.99E-09 cIGF1R-His 2.76E+04 2.37E-04 8.57E-09

[00213] The results showed that the anti-IGF1R antibodies 12A4, 12D1, 10D1 and 10G1 showed good binding affinities to human IGF1R and monkey IGF1R. Example 4. Blocking the binding of human IGF-1 / 2 and IGF1R

[00214] Blocking assays were performed to determine whether anti-IGF1R antibodies can block the binding between IGF1R and its ligands IGF-1 and IGF-2. Specifically, microwell plates were coated with 100 μL / well of hIGF1R-His at 5 μg / mL in carbonate buffer at pH 9.6 overnight at 4 °C. The plates were blocked with 200 μL / well of 1% bovine serum albumin and incubated at 37 °C for 2 hours. Serially diluted anti-IGF1R antibodies (0.005-10 μg / mL in 3-fold serial dilution plus blank buffer) were added to the plates at 100 μL / well. After incubation for 1.5 hours, Biotinylated Human IGF-I Protein (Acro Biosystems, Cat. No.: IG1-H82F7) or biotinylated human IGF-I protein was replaced with Biotinylated Human IGF-II Protein (Acro Biosystems, Cat. No.: IG2-H82Q6) and added to the plates at 100 μL / well. After incubation for 1.5 hours at 37 °C, Streptavidin HRP (Biolegend, Cat. No.) was added.°: 405210) at a 1:3000 dilution was applied to plates at 100 μL / well, and the plates were incubated for 1 hour. The plates were washed 5 times, and 100 μL of TMB was added to each well, and the plates were incubated for 10 minutes. Then, 100 μL of 1M phosphoric acid was added to each well, and the ELISA plates were read at a wavelength of 450 / 570 nm. A fitting curve was obtained using Log (antibody concentration (M)) as the X-axis and chemiluminescence intensity as the Y-axis. IC50 values ​​were calculated, and the results are shown in the table below. Petition 870250090556, dated 03 / 10 / 2025, pages 172 / 204 79 / 88 Table 6 IGF-1 Antibody IGF-2 IC50 (nM) Maximum Inhibition (%) (10 μg / mL) IC50 (nM) Maximum Inhibition (%) (10 μg / mL) ISO — — — — Teprotumumab Analog 1.5 45% 0.9 70% 12A4 2.0 50% 1.9 81% 12D1 2.2 55% 1.6 88% 10D1 1.3 47% 1.7 76% 10G1 1.6 43% 5.2 73%

[00215] All, 12A4, 12D1, 10D1 and 10G1, blocked the binding of IGF-1 / 2 to IGF1R with strong inhibitory effects. Example 5. Internalization of IGF1R induced by anti-IGF1R

[00216] Anti-IGFIR antibodies (3 μg / mL) were added and Secondary Anti-Human Goat IgG Antibody pHAb-AffiniPure Fab to NCI-H838 cells (human lung cells, Procell Life Science & Technology Co., Ltd., Cat. No.: CL-0406). After incubation for 3 hours, the cells were centrifuged and washed with PBS buffer. MFI was detected by flow cytometry, and EC50 was calculated using serially diluted antibodies.

[00217] The results are shown in Figure 1 and in Table 7 below showed that 12A4, 12D1, 10D1, and 10G1 exhibited endocytosis rates comparable to those of the positive control teprotumumab analog in NCI-H838 cells. Table 7 EC50 Antibody (nM) ISO — Teprotumumab Analog 0.76 12A4 0.92 12D1 0.66 10D1 0.51 10G1 1.12 Example 6. Analysis of anti-IGF1R antibody epitopes

[00218] Epitope binding assays were performed Petition 870250090556, dated 03 / 10 / 2025, pages 173 / 204 80 / 88 using the Biacore™ 8K biosensor to determine whether two anti-IGF1R antibodies target the same epitopes or overlapping epitopes. Diluted HBS-EP+ buffer 1* (10 mM 4-(2-hydroxyethyl)-1-piperazinoethanesulfonic acid (HEPES), 150 mM NaCl, 3 mM ethylenediaminetetraacetic acid (EDTA), and 0.05% P20, pH 7.4) was used as running buffer throughout the experiment. Approximately 50 RU of hIGF1R-His were captured at a flow rate of 10 pL / min, and 200 nM of the test antibody (Analyte 1) were injected at a flow rate of 30 pL / min to bind the ligand. Another comparison antibody (Analyte 2) was injected under the same conditions to determine if the binding of different antibodies interfered with each other. The binding time was 180 s for each antibody.

[00219] The binding value of each antibody was obtained using Biacore Insight Evaluation (Version:2.0.15.12933). To quantify the interference of one antibody binding to another, a binding ratio was calculated to compare each pair of antibodies. The binding ratio is defined as the binding value of the second antibody (Analyte 2) divided by the binding value of the first antibody (Analyte 1). The threshold for determining blocking or non-blocking is 0.3. The results were summarized in the table below, which showed that 12A4, 12D1, 10D1, 10G1 and the positive control recognize the same epitope or overlapping epitopes. Table 8 Analyte 1 Analyte 2 12A4 12D1 10D1 10G1 Teprotumumab Analog 12A4 -0.01 -0.02 -0.05 -0.01 0.01 12D1 0.00 -0.01 -0.04 0.00 0.01 10D1 0.02 0.02 -0.02 0.02 0.03 10G1 -0.03 -0.02 -0.04 -0.01 -0.03 Teprotumumab Analog 0.04 0.05 0.02 0.05 0.00 Petition 870250090556, dated 03 / 10 / 2025, pages 174 / 204 81 / 88 Example 7. IGF-1-induced proliferation inhibition

[00220] NCI-H838 cells were seeded in well plates at 5,000 cells per well. After 24 hours of incubation, serially diluted anti-IGF1R antibodies (maximum concentration: 10 pg / mL, 5-fold dilutions, 8 gradients) were added to each well and incubated at 4 °C for 1 hour before the addition of IGF-1 protein. After 72 hours of incubation, the cells were collected and mixed with CellCounting-Lite 2.0 Luminescent Cell Viability Assay (Vazyme, Cat. No.: DD1101) and tested in a microplate reader. The IC50 was calculated, and the results are shown in the table below. Table 9 Antibody IC50 (nM) Maximum inhibition (%) (10 μg / mL) Teprotumumab analog 0.400 85% 12A4 0.045 105% 12D1 0.064 145% 10D1 0.140 117% 10G1 0.091 88%

[00221] The results indicated that 12A4, 12D1 and 10D1 showed almost complete inhibition, with maximum inhibition of more than 100%. Example 8. Inhibition of IGF1R autophosphorylation

[00222] The experiment was performed to test whether anti-IGF1R antibodies can inhibit IGF1R phosphorylation. Specifically, CHO-S-hIGF1R cells (2.4*10⁶ cells / mL) were added to a 96-well plate. The anti-IGF1R antibody was added and incubated at 37°C for 15 min. Then, IGF-1 protein was added to each well and incubated for 10 min. After 5 minutes of centrifugation, the supernatant was removed. 50 μL of lysis buffer (with protease and phosphatase inhibitors) was added to each well and incubated for 30 minutes on ice. After washing with PBS and Petition 870250090556, dated 03 / 10 / 2025, pages 175 / 204 After centrifugation for 5 min, the sample was transferred to an ELISA plate. Phosphorylated IGF1R levels were measured using the IGF1 Phosphotyrosine Receptor ELISA Kit (Abcam, Cat. No.: ab279824), according to the manufacturer's instructions. The mean absorbance for each antibody was determined, and the IC50 was calculated.

[00223] The results are shown in Figures 2A to 2B and Table 10 below, which demonstrated that 12A4, 12D1, 10D1 and 10G1 exhibited a comparable inhibitory effect (e.g., IC50, up to 2 times) on IGF1R phosphorylation compared to the teprotumumab analog positive control. Table 10 Antibody IC50 (nM) Teprotumumab Analog 0.7 12A4 0.9 12D1 1.3 10D1 1.4 10G1 1.2 Example 9. Inhibition of IGF-1-induced OPN secretion

[00224] Thyroid eye disease (TOD) is characterized by swelling and inflammation of the orbital and periorbital tissues with widely varying manifestations. The interaction between TSHR and IGF1R has been studied in the context of TOD pathogenesis. Activation of TSHR and IGF1R in orbital fibroblasts and fibrocytes leads to their differentiation into adipocytes, capable of secreting inflammatory cytokines and hyaluronic acid and proliferating. In human U2OS-TSHR osteosarcoma cells (expressing IGF1R and TSHR), TSHR couples to IGF1R to induce upregulation of genes associated with osteoblast activity (e.g., Osteopontin (OPN)).

[00225] The experiment was performed to test whether anti-IGFIR antibodies can inhibit IGF-1-induced OPN secretion. Specifically, U2OS-TSHR cells (3*104 cells / mL) were added. Petition 870250090556, dated 03 / 10 / 2025, pages 176 / 204 83 / 88 cells were obtained by transfecting U-2OS cells (ATCC, Cat. No.: HTB-96, endogenously expressing high levels of human IGF-1R) with a plasmid expressing human TSHR (SEQ ID NO: 54) into a 24-well plate. Anti-IGF1R or human IgG1 antibody (as ISO control) was added and incubated at 37 °C for 24 hours. Then, IGF-1 protein was added to each well to induce OPN secretion for 24 hours. Cells were collected and centrifuged for 7 days. OPN secretion levels were measured using the Quantikine Human Osteopontin (OPN) ELISA Kit (R&D systems, Cat. No.: PDOST00), according to the manufacturer's instructions. ELISA plates were read at a wavelength of 450 nm. A fitting curve was obtained using Log (antibody concentration (M)) as the X-axis and human OPN level (ng / mL) as the Y-axis. IC50 values ​​were calculated, and the results are shown in Figure 3 and Table 11 below. Table 11 Antibody IC50 (nM) Teprotumumab Analog 0.043 12A4 0.068 12D1 0.096 10D1 0.046 10G1 0.130

[00226] The results showed that 12A4, 12D1, 10D1 and 10G1 effectively inhibited IGF-1-stimulated OPN secretion. Specifically, 12A4, 10D1, and 10G1 showed an inhibitory effect comparable to that of the teprotumumab analogue positive control. Example 10. Pharmacokinetic (PK) Analysis

[00227] The pharmacokinetic clearance rates of anti-IGFIR antibodies were determined in B-hFcRn mice (Biocytogen, Cat. No.: 110001). Specifically, mice were placed into different groups (3 mice per group) and received 3 mg / kg of anti-IGF1R antibodies by intravenous injection. Serum samples were Petition 870250090556, dated 03 / 10 / 2025, pages 177 / 204 84 / 88 collected 4 days before administration and 15 minutes, 1 day, 2 days, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days and 42 days after administration.

[00228] Serum levels of human antibodies were determined by sandwich ELISA. Briefly, Goat Anti-Human IgG (H+L) (Jackson ImmunoResearch Inc., Cat. No.: 109-005-088) was diluted to a final concentration of 2000 ng / mL, added to a 96-well plate (ELISA plate) at 100 pL / well, and then incubated overnight at 4 °C. After incubation, the plate was washed with PBS-T buffer (PBS supplemented with Tween™ 20) 4 times. Areas not bound to the antibody were blocked with 2% BSA (bovine serum albumin) for 2 hours at 37 °C. Then, the plate was washed with PBS-T buffer 4 times. After washing, 100 pL of serum sample was added to each well. The wells were sealed and incubated at 37 °C for 1 hour. After washing the plate using a plate washer, Peroxidase AffiniPure F(ab')2Goat Anti-Human IgG Fragment, specific for Fcy fragment (Jackson ImmunoResearch Inc., n.(Cat. No.: 109-036-098) was added at 100 pL / well to each well of the plate and incubated at 37 °C for 1 hour. After washing the plate, tetramethylbenzidine (TMB) solution was added at 100 pL / well to the 96-well plate as a substrate. After incubation at room temperature in the dark, 100 pL of stopping solution (Beyotime, Cat. No.: P0215) was added to each well. A microplate reader was used to read the absorbance value of each well at wavelengths of 450 nm and 630 nm. Gen5™ data analysis software was used to analyze the data. The absorbance value and the corresponding concentration of the calibration sample prepared for each test product were used to create a standard curve with four parameters (i.e., T1 / 2, Cmax, AUCc-42 days, and CL). The standard curve was used to calculate the antibody concentration of each serum sample.A drug concentration versus time curve was created using the sample concentration calculated at each time point. Petition 870250090556, dated 03 / 10 / 2025, pages 178 / 204 85 / 88 Phoenix™ WinNolin 8.3 was used to calculate the pharmacokinetic parameters. The results are shown in Table 12 below. Table 12 Group T1 / 2 (day) Cmax ^g / mL) AUC0-42 days (day*μg / mL) CL (mL / day / kg) Teprotumumab Analog 9.80±0.25 58.60±17.97 383.08±33.18 7.53±0.64 12A4-QL 14.28±1.55 56.93±17.55 480.82±48.44 5.47±0.46 12A4-YTE 17.86±1.07 85.78±4.18 668.88±2.22 3.68±0.08 12D1-QL 16.95±2.28 55.70±3.0 365.91±31.66 7.09±0.89 12D1-YTE 13.86±2.17 78.32±3.81 509.89±31.54 5.16±0.38 10D1-QL 15.22±2.45 49.78±18.68 316.22±78.16 7.94±1.78 10D1-YTE 15.69±0.61 74.53±3.92 519.62±4.59 4.88±0.10 10G1-YTE 16.97±1.16 77.52±5.69 572.03±22.90 4.34±0.12 T1 / 2: Terminal half-life; Cmax: Maximum concentration; AUC0-42 days: Area under the blood concentration-time curve from 0-42 days; CL: Clearance

[00229] Four days prior to antibody administration, the antibody concentration was detected as 0 μg / mL (results not shown). As shown in Figure 4 and Table 12, the results were consistent with typical pharmacokinetic characteristics, showing that after injection of anti-IGF1R antibodies, the serum antibody concentration in hFcRn mice decreased over time. The tested antibodies exhibited longer half-lives and reduced clearance compared to the positive control with a teprotumumab analogue. Example 11. Stability of anti-IGFIR antibodies

[00230] The experiment was conducted to test the stability of anti-IGF1R antibodies. Anti-IGF1R antibodies were altered to buffer (20 mM His, 140 mM Arg-HCl, pH 5.5) by UF / DF, and their concentration was greater than 100 mg / mL. Subsequently, the antibodies were stored under stress storage at 40 °C for 4 weeks. Potential molecular variants were measured using SEC-HPLC (TOSOH TSKgel G3000 SWXL, Petition 870250090556, dated 03 / 10 / 2025, pp. 179 / 204 86 / 88 7.8 mm x 30 cm, 5 μm).

[00231] The results are shown in Table 13 below. There is no significant decreasing trend in the main peak value, demonstrating that 12A4, 12D1, 10G1, and 10D1 exhibit good stability at high concentrations. Table 13 Antibody T 0 4 weeks HMW Main peak LMW HMW Main peak LMW 12D1 3.5% 96.5% ND 3.4% 92.8% 3.8% 12D1-QL 3.7% 96.3% ND 3.6% 92.5% 3.9% 12D1-YTE 3.4% 96.6% ND 4.1% 91.0% 5.0% 12A4-QL 5.5% 94.5% ND 4.9% 89.3% 5.8% 10D1-YTE 6.5% 93.5% ND 5.7% 87.8% 6.6% 10G1-QL 6.8% 93.2% ND 6.1% 85.4% 8.5% ND: Not detected HMW: High molecular weight LMW: Low molecular weight Example 12. ADCC Activity Test

[00232] The experiment was conducted to test the activity ADCC (antibody-dependent cellular cytotoxicity) of anti-IGF1R antibodies. Specifically, FcR-TANK effector cells and Du145 target cells in a 2:1 E:T ratio were co-incubated with serially diluted anti-IGF1R antibodies for 24 hours, and then the supernatant was collected to test for cell death. Lactate dehydrogenase (LDH) activity released from the cytosol of damaged cells was measured by a non-radioactive colorimetric assay using the Cytotoxicity Detection Kit (Roche, Cat. No.: 04744926001). An antibody with ADCC activity and targeting unrelated targets was used as a reference antibody. The results are shown in Figure 5, which showed that all anti-IGF1R antibodies tested did not exhibit ADCC effect.

[00233] In addition, the levels of IFN-γ cytokine release Petition 870250090556, dated 03 / 10 / 2025, pages 180 / 204 87 / 88 in the same supernatant from the ADCC assay were tested by ELISA. The results are shown in Figure 6. The groups treated with 12A4-YTE and 12D1-QL showed no changes in cytokine levels, while the group treated with the teprotumumab analog showed an increase in IFNγ levels, indicating that 12A4-YTE and 12D1-QL had a better safety profile. Example 13. HA (hyaluronan) release test

[00234] Dolt-onset hyperplasia (DOT) is a debilitating disease characterized by the accumulation of adipocytes and hyaluronan (HA) in the orbital space. HA production by orbital fibroblasts leads to notable increases in tissue volume and anterior displacement of the eyes. Fibroblasts isolated from the periorbital space of DOT patients were used to test the effect of anti-IGF1R antibodies on HA release. Specifically, fibroblast cells were cultured to confluence. The cells were then seeded in a 96-well plate. The following day, serially diluted anti-IGF1R antibodies (5-fold, highest concentration of 50 μg / mL) were added to each well. Human IgG1 was used as an ISO control. IGF-1 was then added to each well. After incubation, the plate supernatant was tested with the HA ELISA kit to detect HA release.Figure 7 shows that 12A4-YTE and 12D1-QL significantly decreased HA release in a dose-dependent manner, with 12A4-YTE producing the greatest repression.

[00235] In a similar experiment, fibroblast cells were seeded in a 96-well plate. The following day, serially diluted anti-IGF1R antibody (3-fold, highest concentration of 2 μg / mL) was added to each well. After incubation with IGF-1, the plate supernatant was tested with the HA ELISA kit to detect HA release. As shown in Figure 8, compared to the positive control with a teprotumumab analog, 12A4-YTE is more effective in reducing HA release levels, indicating the stimulating potential of therapies for DOT. Petition 870250090556, dated 03 / 10 / 2025, pages 181 / 204 88 / 88 OTHER MODALITIES

[00236] It should be understood that, although the invention has been described in conjunction with the detailed description thereof, the preceding description is intended to illustrate, and not limit, the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. Petition 870250090556, dated 03 / 10 / 2025, pp. 182 / 204

Claims

1 / 15 Claims 1. ANTIBODY, or antigen-binding fragment thereof, that binds to insulin-like growth factor receptor 1 (IGF1R), characterized by comprising: a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3, wherein the CDR1 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR1, the CDR2 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR2, and the CDR3 region of the VH comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VH CDR3; and a variable light chain (VL) region comprising CDRs 1, 2 and 3, wherein the CDR1 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected CDR1 of the VL,the CDR2 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VL CDR2, and the CDR3 region of the VL comprises an amino acid sequence that is at least 80% identical to an amino acid sequence of the selected VL CDR3, wherein the amino acid sequences of the selected VH CDRs 1, 2 and 3 and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are one of the following: (1) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 1, 2 and 3, respectively, and the amino acid sequences of the selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 4, 5 and 6, respectively; Petition 870250090556, dated 03 / 10 / 2025, p. 183 / 204 2 / 15 (2) the amino acid sequences of the selected VH CDRs 1, 2 and 3 are shown in SEQ ID NOs: 25, 26 and 27, respectively, and the amino acid sequences of CDRs 1,(3) the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 4, 5 and 6, respectively; (3) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 7, 8 and 9, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 10, 11 and 12, respectively; (4) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 28, 29 and 30, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 10, 11 and 12, respectively; (5) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 13, 14 and 15, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 16, 17 and 18, respectively; (6) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 31, 32 and 33,respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 16, 17 and 18, respectively; (7) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 19, 20 and 21, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 22, 23 and 24, respectively; (8) the amino acid sequences of selected VH CDRs 1, 2 and 3 are presented in SEQ ID NOs: 34, 35 and 36, respectively, and the amino acid sequences of selected VL CDRs 1, 2 and 3 are presented in SEQ ID NOs: 22, 23 and 24, respectively. Petition 870250090556, dated 03 / 10 / 2025, p. 184 / 204 3 / 15 2. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 1, 2 and 3, respectively, and the VL comprising CDRs 1,2 and 3 with the amino acid sequences presented in SEQ ID NOs: 4, 5 and 6, respectively, according to Kabat's definition.

3. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 7, 8 and 9, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively, according to Kabat's definition.

4. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 13, 14 and 15, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively, according to Kabat's definition.

5. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 19,20 and 21, respectively, and the VL comprises CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively, according to Kabat's definition.

6. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 25, 26 and 27, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 4, 5 and 6, respectively, according to Chothia's definition. Petition 870250090556, dated 03 / 10 / 2025, p. 185 / 204 4 / 15 7. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 28, 29 and 30, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively, according to the definition of Chothia.

8. ANTIBODY, according to claim 1,characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 31, 32 and 33, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively, according to the definition of Chothia.

9. ANTIBODY, according to claim 1, characterized by the VH comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 34, 35 and 36, respectively, and the VL comprising CDRs 1, 2 and 3 with the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively, according to the definition of Chothia.

10. ANTIBODY, according to any one of claims 1 to 9, characterized in that the antibody, or antigen-binding fragment thereof, binds specifically to human IGF1R or monkey IGF1R.

11. ANTIBODY, according to any one of claims 1 to 10,characterized by the antibody or antigen-binding fragment being a human or humanized antibody or antigen-binding fragment thereof (e.g., a human IgG1 or IgG4 antibody).

12. ANTIBODY, according to any one of claims 1 to 11, characterized by the antibody or antigen-binding fragment being a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody).

13. NUCLEIC ACID, characterized by comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 1, 2 and 3, respectively, and wherein the VH,when paired with a variable light chain (VL) region comprising the amino acid sequence shown in SEQ ID NO: 38, it binds to IGF1R; (2) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 4, 5 and 6, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 37, binds to IGF1R; (3) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 25, 26 and 27, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 38, binds to IGF1R; (4) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: Petition 870250090556, of 03 / 10 / 2025, page 187 / 204 6 / 15 7, 8 and 9, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 40, binds to IGF1R; (5) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 39, binds to IGF1R; (6) an immunoglobulin heavy chain, or a fragment thereof comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 28, 29 and 30, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 40, binds to IGF1R; (7) an immunoglobulin heavy chain, or a fragment thereof comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 13, 14 and 15, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 42, binds to IGF1R; (8) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 41, binds to IGF1R; Petition 870250090556, dated 03 / 10 / 2025, p. 188 / 204 7 / 15 (9) an immunoglobulin heavy chain, or a fragment thereof comprising a variable heavy chain (VH) region comprising complementarity-determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 31, 32 and 33, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 42, binds to IGF1R; (10) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain (VH) region comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 19, 20 and 21, respectively, and wherein the VH, when paired with a variable light chain (VL) region comprising the amino acid sequence presented in SEQ ID NO: 44, binds to IGF1R; (11) an immunoglobulin light chain, or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence presented in SEQ ID NO: 43, binds to IGF1R; or (12) an immunoglobulin heavy chain, or a fragment thereof, comprising a variable heavy chain region (VH) comprising complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 34, 35 and 36, respectively, and wherein the VH, when paired with a variable light chain region (VL) comprising the amino acid sequence presented in SEQ ID NO: 44, binds to IGF1R.

14. NUCLEIC ACID, according to claim 13, characterized by the nucleic acid comprising a polynucleotide that Petition 870250090556, dated 03 / 10 / 2025, page.189 / 204 8 / 15 encodes a polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 1, 2 and 3, respectively, or SEQ ID NOs: 25, 26, and 27, respectively.

15. NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 4, 5 and 6, respectively. 16.NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 7, 8 and 9, respectively, or SEQ ID NOs: 28, 29 and 30, respectively.

17. NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 10, 11 and 12, respectively. 18.NUCLEIC ACID, according to claim 13, characterized by the nucleic acid comprising a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID Nos: 13, 14 and 15, respectively, or SEQ ID Nos: 31, 32 and 33, respectively.

19. NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 16, 17 and 18, respectively. 20.NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain, or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 19, 20 and 21, respectively, or SEQ ID NOs: 34, 35, and 36, respectively.

21. NUCLEIC ACID, according to claim 13, characterized in that the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences presented in SEQ ID NOs: 22, 23 and 24, respectively. 22.NUCLEIC ACID, according to any one of claims 13 to 21, characterized in that VH, when paired with VL, specifically binds to human IGF1R or monkey IGF1R, or VL, when paired with VH, specifically binds to human IGF1R or monkey IGF1R.

23. NUCLEIC ACID, according to any one of claims 13 to 22, characterized in that the immunoglobulin heavy chain, or a fragment thereof, is a human or humanized immunoglobulin heavy chain, or a fragment thereof (for example, a human IgG1 heavy chain or a fragment thereof), and the immunoglobulin light chain, or a fragment thereof, is a human or humanized immunoglobulin light chain or a fragment thereof. 24.NUCLEIC ACID, according to any one of claims 13 to 23, characterized in that the nucleic acid encodes a single-stranded variable fragment (scFv), a multispecific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR).

25. NUCLEIC ACID, according to any one of claims 13 to 24, characterized in that the nucleic acid is cDNA.

26. VECTOR, characterized in that it comprises one or more nucleic acids, as defined in any one of claims 13 to 25.

27. VECTOR, characterized in that it comprises two of the nucleic acids, as defined in any one of claims 13 to 25, wherein the vector encodes the VH region and the VL region which together bind to IGF1R.

28. VECTOR PAIR, characterized in that each vector comprises one of the nucleic acids, as defined in any one of claims 13 to 25, wherein, together, the vector pair encodes the VH region and the VL region which, together, bind to IGF1R. 29.CELL, characterized by comprising the vector, as defined in any one of claims 26 to 27, or the pair of vectors, as defined in claim 28.

30. CELL, according to claim 29, characterized in that the cell is a CHO cell.

31. CELL, characterized by comprising one or more nucleic acids, as defined in any one of claims 13 to 25. Petition 870250090556, dated 10 / 03 / 2025, pp. 192 / 204 11 / 15 32. CELL, characterized by comprising two of the nucleic acids, as defined in any one of claims 13 to 25.

33. CELL, according to claim 32, characterized in that the two nucleic acids together encode the VH region and the VL region which together bind to IGF1R. 34.METHOD FOR PRODUCING AN ANTIBODY, or an antigen-binding fragment thereof, characterized by comprising: (a) culturing the cell, as defined in any one of claims 29 to 33, under conditions sufficient for the cell to produce the antibody or the antigen-binding fragment; and (b) collecting the antibody or the antigen-binding fragment produced by the cell. 35.ANTIBODY, or antigen-binding fragment thereof, that binds to IGF1R, characterized by comprising: a variable heavy chain (VH) region comprising an amino acid sequence that is at least 80% identical to a selected VH sequence, and a variable light chain (VL) region comprising an amino acid sequence that is at least 80% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 37, and the selected VL sequence is SEQ ID NO: 38; (2) the selected VH sequence is SEQ ID NO: 39, and the selected VL sequence is SEQ ID NO: 40; (3) the selected VH sequence is SEQ ID NO: 41, and the selected VL sequence is SEQ ID NO: 42; and (4) the selected VH sequence is SEQ ID NO: 43, and the selected VL sequence is SEQ ID NO:

44. Petition 870250090556, dated 03 / 10 / 2025, pp. 193 / 204 12 / 15 36.ANTIBODY, according to claim 35, characterized in that the VH comprises the sequence SEQ ID NO: 37 and the VL comprises the sequence SEQ ID NO:

38.

37. ANTIBODY, according to claim 35, characterized in that the VH comprises the sequence SEQ ID NO: 39 and the VL comprises the sequence SEQ ID NO:

40.

38. ANTIBODY, according to claim 35, characterized in that the VH comprises the sequence SEQ ID NO: 41 and the VL comprises the sequence SEQ ID NO:

42.

39. ANTIBODY, according to claim 35, characterized in that the VH comprises the sequence SEQ ID NO: 43 and the VL comprises the sequence SEQ ID NO:

44.

40. ANTIBODY, according to any one of claims 35 to 39, characterized in that the antibody or antigen-binding fragment binds specifically to human IGF1R or Monkey IGF1R. 41.ANTIBODY, according to any one of claims 35 to 40, characterized in that the antibody or antigen-binding fragment is a human or humanized antibody, or antigen-binding fragment thereof.

42. ANTIBODY, according to any one of claims 35 to 41, characterized in that the antibody or antigen-binding fragment is a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody).

43. ANTIBODY, or antigen-binding fragment thereof, characterized in that it cross-competes with the antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 42.

44. ANTIBODY, or antigen-binding fragment thereof, that binds to IGF1R, characterized in that it comprises: Petition 870250090556, dated 03 / 10 / 2025, p.194 / 204 13 / 15 a variable heavy chain (VH) region comprising VH CDR1, VH CDR2 and VH CDR3, which are identical to VH CDR1, VH CDR2 and VH CDR3 of a selected VH sequence; and a variable light chain (VL) region comprising VL CDR1, VL CDR2 and VL CDR3 which are identical to VL CDR1, VL CDR2 and VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 37, and the selected VL sequence is SEQ ID NO: 38; (2) the selected VH sequence is SEQ ID NO: 39, and the selected VL sequence is SEQ ID NO: 40; (3) the selected VH sequence is SEQ ID NO: 41, and the selected VL sequence is SEQ ID NO: 42; and (4) the selected VH sequence is SEQ ID NO: 43, and the selected VL sequence is SEQ ID NO:

44. 45.ANTIBODY-DRUG CONJUGATE, characterized by comprising the antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, covalently linked to a therapeutic agent.

46. CONJUGATE, as defined in claim 45, characterized in that the therapeutic agent is a cytotoxic or cytostatic agent.

47. METHOD OF TREATING AN INDIVIDUAL WITH CANCER, characterized by comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, or the antibody-drug conjugate, as defined in any one of claims 45 to 46, to the individual. Petition 870250090556, dated 03 / 10 / 2025, p. 195 / 204 14 / 15 48. METHOD, according to claim 47, characterized in that the individual has breast cancer, prostate cancer or lung cancer. 49.METHOD, according to any one of claims 47 to 48, characterized by further comprising the administration of a therapeutically effective amount of an anti-CD3 antibody, an anti-PD1 antibody, an anti-PDL1 antibody, an anti-HER2 antibody and / or an anti-EGFR antibody, to the individual.

50. METHOD FOR REDUCING TUMOR GROWTH RATE, characterized by comprising: placing a tumor cell in contact with an effective amount of a composition comprising an antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, or the antibody-drug conjugate, as defined in any one of claims 45 to 46. 51.METHOD FOR KILLING A TUMOR CELL, characterized by comprising: placing a tumor cell in contact with an effective amount of a composition comprising the antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, or the antibody-drug conjugate, as defined in any one of claims 45 to 46.

52. METHOD FOR TREATING AN INDIVIDUAL WITH AN EYE DISEASE OR DISORDER, characterized by comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, or the antibody-drug conjugate, as defined in any one of claims 45 to 46, to the individual. Petition 870250090556, dated 03 / 10 / 2025, p. 196 / 204 15 / 15 53. METHOD, according to claim 52, characterized in that the individual has thyroid eye disease (TOD). 54.A METHOD FOR TREATING AN INDIVIDUAL WITH A BONE DISEASE OR DISORDER, characterized by comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, or the antibody-drug conjugate, as defined in any one of claims 45 to 46, to the individual.

55. PHARMACEUTICAL COMPOSITION, characterized by comprising the antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44, and a pharmaceutically acceptable carrier.

56. PHARMACEUTICAL COMPOSITION, characterized by comprising the antibody-drug conjugate, as defined in any one of claims 45 to 46, and a pharmaceutically acceptable carrier. 57.A chimeric antigen receptor (CAR), characterized by comprising the antibody, or antigen-binding fragment thereof, as defined in any one of claims 1 to 12 or 35 to 44. Petition 870250090556, dated 10 / 03 / 2025, pp. 197-204.

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