Invention and use of FOLR1-specific antibody

Abstract

The present application relates to an antibody specifically recognizing FOLR1, a preparation method therefor, and uses thereof. The present application further relates to an antibody-drug conjugate (ADC) targeting FOLR1 and a composition containing said molecules. Additionally, the present application further relates to therapeutic and diagnostic uses of the antibody, antibody fragments, and the antibody-drug conjugate.

Description

Invention and application of anti-FOLR1 specific antibodies Technical Field

[0001] The present application relates to antibodies that specifically recognize FOLR1, methods for their preparation, and uses. The present application also relates to antibody-drug conjugates (ADCs) targeting FOLR1 and compositions containing such ADCs. Furthermore, the present invention also relates to therapeutic and diagnostic uses of these antibodies, antibody fragments, and ADCs. Background Art

[0002] It is estimated that in 2020, there will be 308,069 new cases of ovarian cancer worldwide, and 193,811 deaths from ovarian cancer (PMID: 26557500). In my country, the annual incidence of ovarian cancer ranks third among female reproductive system tumors, showing an increasing trend year by year, and the mortality rate ranks first among female reproductive tract malignant tumors. It is a malignant tumor that seriously threatens women's health. Although the disease is initially sensitive to chemotherapy and most patients can achieve relief with first-line platinum chemotherapy, up to 80% of patients will eventually relapse and require further treatment. Patients who are sensitive to platinum treatment eventually become resistant to platinum chemotherapy after multiple relapses. For platinum-resistant recurrent ovarian cancer (ROC), the efficacy of platinum retreatment is <10%, and the prognosis is extremely poor. Therefore, the treatment of platinum-resistant ROC is the most difficult problem in the clinical treatment of ovarian cancer, which seriously affects the prognosis of ovarian cancer patients.

[0003] Folic acid, an essential vitamin for the human body, must be taken up from the outside world and transported into cells through endocytosis, mediated by folate receptors (FRs). There are four subtypes of folate receptors: folate receptor α (FRα, also known as folate receptor 1 (FOLR1)), folate receptor β (FRβ, also known as folate receptor 2 (FOLR2)), folate receptor γ (FRγ, also known as folate receptor 3 (FOLR3)), and folate receptor δ (FRδ, also known as folate receptor 4 (FOLR4)).

[0004] Folate receptor α is a 38-40 kDa glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein (PMID: 2557328), encoded by the FOLR1 gene. It is a member of the high-affinity folate receptor (FR) family. It specifically binds to 5-methyltetrahydrofolate and free folate, participating in cellular folate uptake via endocytosis (PMID: 1968465). FRα is absent in most normal tissues, with the exception of low expression in the kidney and lung (PMID: 1596899). FRα is highly expressed in various tumors, including ovarian cancer, triple-negative breast cancer, endometrial cancer, mesothelioma, and lung cancer (PMID: 25349970, PMID: 15745749, PMID: 32152484). In addition, FRα is persistently expressed in metastases and recurrent cancers of ovarian cancer patients, as well as in epithelial ovarian and endometrial cancers after chemotherapy (PMID: 18222534, PMID: 23558051, PMID: 25904506). FRα overexpression is also associated with tumor cell migration and invasion (PMID: 12776159, PMC3492371).

[0005] Antibody-Drug Conjugates (ADCs) are derivatives of traditional antibody drugs. They are composed of monoclonal antibodies targeting specific antigens and small molecule cytotoxic drugs coupled via linkers. They combine the targeting specificity of antibodies with the powerful killing effects of traditional small molecule drugs. Their main indication is malignant tumors. ADCs have the potential to combine the favorable pharmacokinetic, biodistribution, and tumor-targeting properties of antibodies with the effective cell-killing mechanism provided by the attached small molecule cytotoxic drug (or payload). ADCs have stringent requirements for target antigens. Targets suitable for ADC development are generally antigens that are highly expressed in tumors and lowly or barely expressed in healthy tissues; and the target antigen should have internalization properties.

[0006] FOLR1 is highly expressed in various tumors, including ovarian cancer, non-small cell lung cancer, and triple-negative breast cancer, and its absence in most normal tissues makes it a promising target for ADC development. Several ADCs targeting FOLR1 have been developed. For example, mirvetuximab soravtansine (also known as IMGN853, trade name Elahere) is an antibody-drug conjugate targeting FOLR1, consisting of an anti-folate receptor α antibody, a cleavable linker, and the maytansine alkaloid DM4. IMGN853 has demonstrated promising efficacy in patients with platinum-resistant ovarian cancer. In patients with platinum-resistant ovarian cancer overexpressing FOLR1 who had previously received bevacizumab, treatment with IMGN853 resulted in an objective response rate (ORR) of 32.4%, a median duration of response (DOR) of 6.9 months, and a median progression-free survival (PFS) of 4.3 months (DOI: 10.1016 / S0090-8258(22)01297-5).

[0007] However, IMGN853 is only effective in patients with high FOLR1 expression, but has no effect on those with moderate to low FOLR1 expression. Furthermore, IMGN853 poses concerns about toxicity. In clinical trials, 31% of patients experienced serious adverse reactions while using IMGN853.

[0008] Therefore, in the field of tumor treatment, there is still an urgent need to develop monoclonal antibodies or ADC drugs targeting FOLR1 with stronger efficacy. This application meets this demand to a certain extent. Summary of the Invention

[0009] In a first aspect, the present invention provides an antibody targeting human FOLR1, which has the following advantages:

[0010] (1) High affinity binding to human FOLR1 and target cells expressing human FOLR1;

[0011] (2) have good cross-activity with cynomolgus monkeys;

[0012] (3) Ability to enter cells via endocytosis;

[0013] (4) does not block the binding of folic acid to the FOLR1 receptor;

[0014] (5) Suitable for constructing effective therapeutic antibody-drug conjugates;

[0015] In one embodiment, the present invention provides an anti-FOLR1 antibody and an antigen-binding fragment thereof that specifically binds to FOLR1, comprising:

[0016] 1) the three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised by the heavy chain variable region as shown in SEQ ID NO: 4 and / or the three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised by the light chain variable region as shown in SEQ ID NO: 8;

[0017] 2) the three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised by the heavy chain variable region as set forth in SEQ ID NO: 12 and / or the three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised by the light chain variable region as set forth in SEQ ID NO: 16;

[0018] 3) the three heavy chain CDRs (HCDR1, HCDR2, HCDR3) contained in the heavy chain variable region as shown in SEQ ID NO: 20 and / or the three light chain CDRs (LCDR1, LCDR2, LCDR3) contained in the light chain variable region as shown in SEQ ID NO: 24; or

[0019] 4) the three heavy chain CDRs (HCDR1, HCDR2, HCDR3) contained in the heavy chain variable region as shown in SEQ ID NO: 28 and / or the three light chain CDRs (LCDR1, LCDR2, LCDR3) contained in the light chain variable region as shown in SEQ ID NO: 32.

[0020] In one embodiment, the present invention provides an anti-FOLR1 antibody and an antigen-binding fragment thereof that specifically binds to FOLR1, comprising:

[0021] 1) HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 1, 2 and 3, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 1, 2 and 3, respectively, or consisting of SEQ ID NOs: 1, 2 and 3; and / or LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 5, 6 and 7, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 5, 6 and 7, respectively, or consisting of SEQ ID NOs: 5, 6 and 7;

[0022] 2) HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 9, 10 and 11, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 9, 10 and 11, respectively, or consisting of SEQ ID NOs: 9, 10 and 11; and / or LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 13, 14 and 15, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 13, 14 and 15, respectively, or consisting of SEQ ID NOs: 13, 14 and 15;

[0023] 3) HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 17, 18 and 19, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 17, 18 and 19, respectively, or consisting of SEQ ID NOs: 17, 18 and 19; and / or LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 21, 22 and 23, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 21, 22 and 23, respectively, or consisting of SEQ ID NOs: 21, 22 and 23; or

[0024] 4) HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 25, 26 and 27, or sequences comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NOs: 25, 26 and 27, respectively, or consisting of SEQ ID NOs: 25, 26 and 27; and / or LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 29, 30 and 31, or sequences comprising one or more and no more than 3 amino acid substitutions (e.g., conservative substitutions), deletions or insertions, relative to SEQ ID NOs: 29, 30 and 31, respectively, or consisting of SEQ ID NOs: 29, 30 and 31.

[0025] In another embodiment, the present invention provides an anti-FOLR1 antibody and an antigen-binding fragment thereof that specifically binds to FOLR1, comprising a heavy chain variable region and / or a light chain variable region, wherein:

[0026] 1) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:4, or a sequence containing one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:4, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, or consists of SEQ ID NO:4; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8, or a sequence containing one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:8, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:8, or consists of SEQ ID NO:8;

[0027] 2) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 12, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO: 12, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 12, or consists of SEQ ID NO: 12; and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 16, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO: 16, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 16, or consists of SEQ ID NO: 16;

[0028] 3) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:20, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:20, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:20, or consists of SEQ ID NO:20, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:24, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:24, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:24, or consists of SEQ ID NO:24; or

[0029] 4) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:28, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:28, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:28, or consists of SEQ ID NO:28; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:32, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:32, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:32, or consists of SEQ ID NO:32;

[0030] 5) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:35, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:35, or consists of SEQ ID NO:35; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:39, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:39, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, or consists of SEQ ID NO:39;

[0031] 6) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:35, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:35, or consists of SEQ ID NO:35; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:40, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:40, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:40, or consists of SEQ ID NO:40;

[0032] 7) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:35, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:35, or consists of SEQ ID NO:35; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:41, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:41, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, or consists of SEQ ID NO:41;

[0033] 8) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:35, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:35, or consists of SEQ ID NO:35; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:42, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:42, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:42, or consists of SEQ ID NO:42;

[0034] 9) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:36, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:36, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:36, or consists of SEQ ID NO:36; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:39, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:39, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, or consists of SEQ ID NO:39;

[0035] 10) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:36, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:36, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:36, or consists of SEQ ID NO:36; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:40, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:40, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:40, or consists of SEQ ID NO:40;

[0036] 11) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:36, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:36, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:36, or consists of SEQ ID NO:36; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:41, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:41, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, or consists of SEQ ID NO:41;

[0037] 12) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:36, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:36, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:36, or consists of SEQ ID NO:36; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:42, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:42, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:42, or consists of SEQ ID NO:42;

[0038] 13) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:37, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:37, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:37, or consists of SEQ ID NO:37; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:39, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:39, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, or consists of SEQ ID NO:39;

[0039] 14) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:37, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:37, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:37, or consists of SEQ ID NO:37; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:40, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:40, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:40, or consists of SEQ ID NO:40;

[0040] 15) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:37, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:37, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:37, or consists of SEQ ID NO:37; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:41, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:41, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, or consists of SEQ ID NO:41;

[0041] 16) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:37, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:37, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:37, or consists of SEQ ID NO:37; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:42, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:42, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:42, or consists of SEQ ID NO:42;

[0042] 17) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:51, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:51, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:51, or consists of SEQ ID NO:51; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0043] 18) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:51, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:51, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:51, or consists of SEQ ID NO:51, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0044] 19) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:51, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:51, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:51, or consists of SEQ ID NO:51; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0045] 20) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0046] 21) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0047] 22) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0048] 23) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0049] 24) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0050] 25) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:52, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:52, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:52, or consists of SEQ ID NO:52, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:60, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:60, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:60, or consists of SEQ ID NO:60;

[0051] 26) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0052] 27) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0053] 28) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0054] 29) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0055] 30) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0056] 31) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:53, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:53, or consists of SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:60, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:60, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:60, or consists of SEQ ID NO:60;

[0057] 32) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:54, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:54, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:54, or consists of SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0058] 33) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:54, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:54, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:54, or consists of SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0059] 34) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:54, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:54, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:54, or consists of SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0060] 35) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:54, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:54, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:54, or consists of SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0061] 36) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:54, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:54, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:54, or consists of SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0062] 37) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:61, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:61, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:61, or consists of SEQ ID NO:61; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0063] 38) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:61, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:61, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:61, or consists of SEQ ID NO:61, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0064] 39) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:61, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:61, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:61, or consists of SEQ ID NO:61, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0065] 40) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:61, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:61, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:61, or consists of SEQ ID NO:61; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0066] 41) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:61, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:61, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:61, or consists of SEQ ID NO:61; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0067] 42) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0068] 43) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0069] 44) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0070] 45) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0071] 46) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0072] 47) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:62, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:62, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62, or consists of SEQ ID NO:62, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:60, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:60, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:60, or consists of SEQ ID NO:60;

[0073] 48) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0074] 49) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0075] 50) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0076] 51) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0077] 52) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0078] 53) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:63, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63, or consists of SEQ ID NO:63, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:60, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:60, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:60, or consists of SEQ ID NO:60;

[0079] 54) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:55, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:55, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, or consists of SEQ ID NO:55;

[0080] 55) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:56, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:56, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:56, or consists of SEQ ID NO:56;

[0081] 56) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:57, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:57, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:57, or consists of SEQ ID NO:57;

[0082] 57) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:58, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:58, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:58, or consists of SEQ ID NO:58;

[0083] 58) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:59, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, or consists of SEQ ID NO:59;

[0084] 59) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64, or consists of SEQ ID NO:64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:60, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:60, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:60, or consists of SEQ ID NO:60;

[0085] 60) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:43, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:43, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43, or consists of SEQ ID NO:43; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:47, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:47, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, or consists of SEQ ID NO:47;

[0086] 61) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:43, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:43, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43, or consists of SEQ ID NO:43; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:48, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:48, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, or consists of SEQ ID NO:48;

[0087] 62) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:43, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:43, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43, or consists of SEQ ID NO:43; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:49, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:49, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:49, or consists of SEQ ID NO:49;

[0088] 63) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:43, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:43, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43, or consists of SEQ ID NO:43; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:50, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:50, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:50, or consists of SEQ ID NO:50;

[0089] 64) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:44, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:44, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44, or consists of SEQ ID NO:44; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:47, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:47, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, or consists of SEQ ID NO:47;

[0090] 65) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:44, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:44, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44, or consists of SEQ ID NO:44; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:48, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:48, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, or consists of SEQ ID NO:48;

[0091] 66) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:44, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:44, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44, or consists of SEQ ID NO:44; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:49, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:49, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:49, or consists of SEQ ID NO:49;

[0092] 67) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:44, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:44, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44, or consists of SEQ ID NO:44; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:50, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:50, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:50, or consists of SEQ ID NO:50;

[0093] 68) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:45, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45, or consists of SEQ ID NO:45; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:47, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:47, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, or consists of SEQ ID NO:47;

[0094] 69) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:45, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45, or consists of SEQ ID NO:45; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:48, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:48, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, or consists of SEQ ID NO:48;

[0095] 70) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:45, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45, or consists of SEQ ID NO:45; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:49, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:49, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:49, or consists of SEQ ID NO:49;

[0096] 71) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:45, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45, or consists of SEQ ID NO:45; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:50, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:50, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:50, or consists of SEQ ID NO:50;

[0097] 72) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:46, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:46, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:46, or consists of SEQ ID NO:46; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:47, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:47, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, or consists of SEQ ID NO:47;

[0098] 73) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:46, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:46, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:46, or consists of SEQ ID NO:46; and the light chain variable region comprises the amino acid sequence of SEQ ID NO:48, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:48, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, or consists of SEQ ID NO:48;

[0099] 74) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:46, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:46, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:46, or consists of SEQ ID NO:46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:49, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:49, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:49, or consists of SEQ ID NO:49; or

[0100] 75) The heavy chain variable region comprises the amino acid sequence of SEQ ID NO:46, or a sequence containing one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO:46, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:46, or consists of SEQ ID NO:46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:50, or a sequence containing one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO:50, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:50, or consists of SEQ ID NO:50.

[0101] In some embodiments, the above-mentioned antibodies or antigen-binding fragments thereof further comprise heavy chain and / or light chain constant region sequences derived from the human antibody germline consensus sequence. The light chain constant region is preferably a human kappa or lambda chain constant region. The heavy chain constant region can be a gamma, mu, alpha, delta, or epsilon chain. In some embodiments, the heavy chain constant region is preferably derived from the constant region sequence of human IgG1, IgG2, IgG3, or IgG4. In one embodiment, the light chain constant region comprises the sequence shown in SEQ ID NO: 34, or consists of the sequence shown in SEQ ID NO: 34. In another embodiment, the heavy chain constant region comprises the sequence shown in SEQ ID NO: 33.

[0102] It will be appreciated that sequence variants of these constant region domains may also be used, for example comprising one or more amino acid modifications, wherein amino acid positions are identified according to the EU index system of Kabat et al. (1991).

[0103] In a specific embodiment, the present invention provides an anti-FOLR1 antibody and an antigen-binding fragment thereof that specifically binds to FOLR1, comprising a heavy chain and / or a light chain, wherein:

[0104] 1) the heavy chain comprises the amino acid sequence of SEQ ID NO:65, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:65, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65, or consists of SEQ ID NO:65, and the light chain comprises the amino acid sequence of SEQ ID NO:66, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:66, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:66, or consists of SEQ ID NO:66;

[0105] 2) the heavy chain comprises the amino acid sequence of SEQ ID NO:67, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:67, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:67, or consists of SEQ ID NO:67, and the light chain comprises the amino acid sequence of SEQ ID NO:68, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:68, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:68, or consists of SEQ ID NO:68;

[0106] 3) the heavy chain comprises the amino acid sequence of SEQ ID NO:69, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:69, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:69, or consists of SEQ ID NO:69, and the light chain comprises the amino acid sequence of SEQ ID NO:70, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:70, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:70, or consists of SEQ ID NO:70;

[0107] 4) the heavy chain comprises the amino acid sequence of SEQ ID NO:71, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:71, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:71, or consists of SEQ ID NO:71, and the light chain comprises the amino acid sequence of SEQ ID NO:72, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:72, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:72, or consists of SEQ ID NO:72;

[0108] 5) the heavy chain comprises the amino acid sequence of SEQ ID NO:73, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:73, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:73, or consists of SEQ ID NO:73, and the light chain comprises the amino acid sequence of SEQ ID NO:74, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:74, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:74, or consists of SEQ ID NO:74;

[0109] 6) the heavy chain comprises the amino acid sequence of SEQ ID NO:75, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:75, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:75, or consists of SEQ ID NO:75, and the light chain comprises the amino acid sequence of SEQ ID NO:76, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:76, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:76, or consists of SEQ ID NO:76;

[0110] 7) the heavy chain comprises the amino acid sequence of SEQ ID NO:77, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:77, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:77, or consists of SEQ ID NO:77, and the light chain comprises the amino acid sequence of SEQ ID NO:78, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:78, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:78, or consists of SEQ ID NO:78;

[0111] 8) the heavy chain comprises the amino acid sequence of SEQ ID NO:79, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:79, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:79, or consists of SEQ ID NO:79, and the light chain comprises the amino acid sequence of SEQ ID NO:80, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:80, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:80, or consists of SEQ ID NO:80;

[0112] 9) the heavy chain comprises the amino acid sequence of SEQ ID NO:81, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:81, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:81, or consists of SEQ ID NO:81, and the light chain comprises the amino acid sequence of SEQ ID NO:82, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:82, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:82, or consists of SEQ ID NO:82;

[0113] 10) the heavy chain comprises the amino acid sequence of SEQ ID NO:83, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:83, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:83, or consists of SEQ ID NO:83, and the light chain comprises the amino acid sequence of SEQ ID NO:84, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:84, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:84, or consists of SEQ ID NO:84;

[0114] 11) the heavy chain comprises the amino acid sequence of SEQ ID NO:85, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:85, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:85, or consists of SEQ ID NO:85, and the light chain comprises the amino acid sequence of SEQ ID NO:86, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:86, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:86, or consists of SEQ ID NO:86;

[0115] 12) the heavy chain comprises the amino acid sequence of SEQ ID NO:87, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:87, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:87, or consists of SEQ ID NO:87, and the light chain comprises the amino acid sequence of SEQ ID NO:88, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:88, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:88, or consists of SEQ ID NO:88;

[0116] 13) the heavy chain comprises the amino acid sequence of SEQ ID NO:89, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:89, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:89, or consists of SEQ ID NO:89, and the light chain comprises the amino acid sequence of SEQ ID NO:90, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions, or any combination thereof, relative to SEQ ID NO:90, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:90, or consists of SEQ ID NO:90; or

[0117] 14) The heavy chain comprises the amino acid sequence of SEQ ID NO:91, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO:91, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:91, or consists of SEQ ID NO:91, and the light chain comprises the amino acid sequence of SEQ ID NO:92, or a sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO:92, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:92, or consists of SEQ ID NO:92.

[0118] In certain embodiments of any of the foregoing antibodies, the antibody is monoclonal.

[0119] In certain embodiments of the antibody of any of the foregoing, the antibody is a full-length antibody.

[0120] In certain embodiments of the antibody of any of the foregoing, the antibody is a chimeric antibody or a humanized antibody.

[0121] In one embodiment, the anti-FOLR1 antibody of the present invention is a complete antibody, such as an IgG1, IgG2, IgG3, or IgG4 antibody. In another embodiment, the anti-FOLR1 antibody of the present invention encompasses only its antigen-binding portion, such as a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0122] In a second aspect, the present invention provides an antibody-drug conjugate targeting human FOLR1, wherein the antibody-drug conjugate has the following advantages:

[0123] (1) Binds to target cells expressing human FOLR1 with high affinity;

[0124] (2) Ability to enter cells through endocytosis and kill target cells; in some embodiments, the ADC of the present invention has high endocytosis efficiency;

[0125] (3) treating or improving a subject's condition associated with abnormal function or expression of FOLR1 (e.g., cancer, such as ovarian cancer, triple-negative breast cancer, endometrial cancer, peritoneal cancer, and lung cancer), or treating or improving one or more symptoms of the disease;

[0126] (4) reducing or inhibiting tumor growth or progression in a subject having a tumor expressing FOLR1;

[0127] (5) Exerts cytotoxic activity in cells expressing FOLR1.

[0128] In one embodiment, the present application provides a conjugate comprising the anti-FOLR1 antibody of the first aspect. In a specific embodiment, the molecule that can be conjugated to the anti-FOLR1 antibody is, for example, a cytotoxic agent, an immunomodulator, an imaging agent, a fluorescent protein, a molecular marker, a therapeutic protein, a biopolymer, and an oligonucleotide.

[0129] In one embodiment, the present invention provides an antibody-drug conjugate (ADC), comprising the anti-FOLR1 antibody or antigen-binding fragment thereof according to the first aspect and at least one therapeutically active substance or pharmaceutically active ingredient, and having the structure of Ab-(LD)n, wherein: Ab is the antibody or antigen-binding fragment thereof that binds to FOLR1 according to the first aspect of the present invention; L is a linker; D is a therapeutically active substance or pharmaceutically active ingredient, and n represents 1-8, for example, 1, 2, 3, 4, 5...

[0130] In one embodiment of the present invention, n represents the number of drug-linker (LD) moieties coupled to a single antibody (Ab), and is preferably an integer from 1 to 8. In this case, the single ADC conjugate may also be referred to as an ADC compound. In any of the embodiments herein, on the ADC compound according to the present invention, there may be 1, 2, 3, 4, 5, 6, 7, or 8 drug-linker moieties coupled to a single antibody.

[0131] In another embodiment of the present invention, n represents the average DAR of the conjugate composition prepared. In this case, n can be, for example, an integer or decimal in the range of 1 to 8, 1.0 to about 8.0, 1.0 to about 7.0, or 1.0 to about 6.6, 2.0 to about 8.0, 2.0 to about 7.5, 2.0 to 6.5, or 2.0 to about 6.0, such as 3.0-4.0, 4.0-5.0, 7.0-8.0. In some aspects, n represents an average DAR of about 3. In some aspects, n represents an average DAR of about 4. In some aspects, n represents an average DAR of about 5. In some aspects, n represents an average DAR of about 6. In some aspects, n represents an average DAR of about 7. In some aspects, n represents an average DAR of about 8.

[0132] IgG1 antibodies have 16 pairs of cysteine ​​residues, present as 12 intrachain and 4 interchain disulfide bonds. The interchain disulfide bonds are solvent-accessible and can be reduced by reducing agents to form eight sulfhydryl groups, which serve as conjugation targets. In one embodiment of the present invention, the linker is conjugated to the sulfhydryl groups of the cysteine ​​residues on the anti-FOLR1 antibody.

[0133] In a specific embodiment, the therapeutically active substance or pharmaceutically active ingredient is a cytotoxin, a plant toxin, a small molecule toxin, a radioisotope, a maytansinoid, or the like. In a specific embodiment, the cytotoxin is dolastatin and its auristatin derivatives, such as monomethyl auristatin E (MMAE). In another specific embodiment, the cytotoxin is a topoisomerase I inhibitor, such as a camptothecin derivative. In a preferred embodiment, the cytotoxin is DXD. In another embodiment, the therapeutically active substance or pharmaceutically active ingredient is MMAE or DXD.

[0134] In one embodiment, the cytotoxin is covalently linked to the anti-FOLR1 antibody or antigen-binding fragment thereof directly or via a linker in a non-site-specific or site-specific manner.

[0135] In one embodiment, the linker is a protease-cleavable peptide linker. In a specific embodiment, the peptide linker comprises a protease-cleavable peptide fragment, such as glycine-glycine-phenylalanine-glycine (GGFG). In a specific embodiment, the peptide linker may further comprise, for example, a maleimide coupled to an antibody cysteine ​​residue.

[0136] In one embodiment, the linker L and the active substance D constitute Deruxtecan.

[0137] In a specific embodiment, the antibody-drug conjugate of the present invention has the following structure:

[0138] In a third aspect, the present invention provides an isolated polynucleotide molecule encoding any one of the antibodies or antigen-binding fragments thereof described in the first aspect.

[0139] In a fourth aspect, the present invention provides a vector comprising the nucleic acid molecule of the third aspect. In one embodiment, the vector is an expression vector.

[0140] In a fifth aspect, the present invention provides a host cell comprising the vector of the fourth aspect or the nucleic acid molecule of the third aspect. In some embodiments, the host cell is prokaryotic, such as Escherichia coli. In other embodiments, the host cell is eukaryotic, such as 293 cells, CHO cells, or yeast cells.

[0141] In a sixth aspect, the present invention provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof or the antibody-drug conjugate of the present invention, a polynucleotide molecule, a vector, a host cell, and a pharmaceutically acceptable carrier.

[0142] In a seventh aspect, the present invention provides a method for preparing the anti-FOLR1 antibody or antigen-binding fragment thereof described herein, the method comprising expressing the antibody or antigen-binding fragment thereof in the host cell described herein under conditions suitable for the expression of the antibody or antigen-binding fragment thereof, and recovering the expressed antibody or antigen-binding fragment thereof from the host cell.

[0143] In an eighth aspect, the present invention provides a method for treating a disease associated with abnormal expression of FOLR1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof, the antibody-drug conjugate, the polynucleotide molecule, the vector, the host cell, and the pharmaceutical composition of the present invention.

[0144] In one embodiment, the disease associated with abnormal expression of FOLR1 is a cancer that highly expresses FOLR1, such as ovarian cancer, triple-negative breast cancer, endometrial cancer, peritoneal cancer, and lung cancer.

[0145] In some embodiments, the antibodies or antigen-binding fragments thereof, antibody-drug conjugates, polynucleotide molecules, vectors, host cells, and pharmaceutical compositions of the present invention can also be administered in combination with one or more other therapies, such as treatment modalities and / or other therapeutic agents, for the purposes described herein, for example, for the treatment of the relevant diseases or conditions mentioned herein.

[0146] In a specific embodiment, the present invention provides a method for killing cells expressing FOLR1 or inhibiting the growth of cells expressing FOLR1, comprising contacting the cells with an effective amount of the antibody or antigen-binding fragment thereof, the antibody-drug conjugate, the polynucleotide molecule, the vector, the host cell, and the pharmaceutical composition of the present invention.

[0147] In a ninth aspect, the present invention provides use of an anti-FOLR1 antibody or an antigen-binding fragment thereof in the preparation of an antibody-drug conjugate for treating cancer.

[0148] In a tenth aspect, the present invention provides use of the anti-FOLR1 antibody or antigen-binding fragment thereof, antibody-drug conjugate, vector, host cell or pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer.

[0149] In some embodiments, the cancer is a cancer that highly expresses FOLR1, such as ovarian cancer, triple-negative breast cancer, endometrial cancer, peritoneal cancer, and lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0150] FIG1 shows a schematic diagram of the structure of the conjugate of anti-FOLR1 chimeric antibody and MMAE.

[0151] FIG2 shows the cytotoxicity of anti-FOLR1 chimeric antibody MMAE conjugates against KB cells.

[0152] Figure 3 shows the nonspecific binding activity of the anti-FOLR1 humanized antibody and its binding activity to mouse FOLR1. Figure 3A shows the binding curve of the anti-FOLR1 humanized antibody to FOLR2, Figure 3B shows the binding curve of the anti-FOLR1 humanized antibody to FOLR3, Figure 3C shows the binding curve of the anti-FOLR1 humanized antibody to FOLR4, and Figure 3D shows the binding curve of the anti-FOLR1 humanized antibody to mouse FOLR1.

[0153] FIG4 shows the results of a blocking experiment of the anti-FOLR1 humanized antibody on the binding between FA-BSA and FOLR1.

[0154] Figure 5 shows the cell cytotoxicity of the anti-FOLR1 humanized antibody MMAE conjugate. Figures AC show the cytotoxicity curves of the anti-FOLR1 humanized antibody MMAE conjugate against KB cells; Figures DF show the cytotoxicity curves of the anti-FORL1 humanized antibody MMAE conjugate against SK-OV-3 cells.

[0155] FIG6 shows a schematic diagram of the structure of the conjugate of anti-FOLR1 humanized antibody and DXD.

[0156] Figure 7 shows that an anti-FOLR1 humanized antibody DXD-conjugated ADC inhibits the growth of human oral epidermoid carcinoma cells. Figure 7A shows that the anti-FOLR1 humanized antibody DXD conjugate inhibits KB tumor growth. Figure 7B shows that treatment with the anti-FOLR1 humanized antibody DXD conjugate does not affect changes in mouse body weight.

[0157] Figure 8 shows that ADCs conjugated with DXD to anti-FOLR1 humanized antibodies inhibited the growth of human lung cancer cells. Figure 8A shows that ADCs conjugated with anti-FOLR1 humanized antibodies inhibited tumor growth. Figure 8B shows that treatment with ADCs conjugated with anti-FOLR1 humanized antibodies did not affect changes in mouse body weight.

[0158] Detailed Description of the Invention

[0159] All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods and examples described herein are illustrative only and are not intended to be limiting. Other features, objects and advantages of the present invention will be apparent from this specification and the accompanying drawings and from the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. For the purposes of the present invention, the following terms are defined below.

[0160] I. Definition

[0161] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0162] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0163] As used herein, the term "comprises" or "includes" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this article, when the term "comprises" or "includes" is used, unless otherwise indicated, it also covers the situation consisting of the stated elements, integers or steps.

[0164] The term "antibody" is used herein in the broadest sense to refer to a protein that contains an antigen binding site.

[0165] The term "immunoglobulin" refers to a protein with the structure of a naturally occurring antibody and is generally used interchangeably with the term "antibody" in this application. IgG immunoglobulins are heterotetrameric glycoproteins consisting of two light chains and two heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each immunoglobulin heavy chain has a heavy chain variable region (VH), also known as a heavy chain variable domain, followed by three heavy chain constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each immunoglobulin light chain has a light chain variable region (VL), also known as a light chain variable domain, followed by a light chain constant domain (CL). In IgG molecules, the VH-CH1 of the heavy chain is usually paired with the VL-CL of the light chain to form a Fab fragment that specifically binds to the antigen. Therefore, an IgG immunoglobulin is essentially composed of two Fab molecules connected by the immunoglobulin hinge region and two dimerized Fc regions. The heavy chains of immunoglobulins can be assigned to one of five classes, called α (IgA), δ (IgD), ε (IgE), γ (IgG), or μ (IgM), based on the type of their constant region, some of which can be further divided into subclasses, such as γ1 (IgG1), γ2 (IgG2), γ3 (IgG3), γ4 (IgG4), α1 (IgA1), and α2 (IgA2). The light chains of immunoglobulins can also be assigned to one of two types, called κ and λ, based on the amino acid sequence of their constant domains.

[0166] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and is capable of binding to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent or bispecific antibodies or fragments thereof; camelid antibodies (heavy chain antibodies); and multispecific antibodies formed from antibody fragments.

[0167] The terms "antigen binding site" and "antigen binding domain" are used interchangeably to refer to the region of an antibody molecule that actually binds to an antigen. Antigen binding sites include, but are not limited to, Fv, Fab fragments, Fab', Fab'-SH, F(ab')2, single-chain antibody molecules (e.g., scFv), VHH, and other formats.

[0168] The term "variable region" or "variable domain" of an antibody refers to the domain of the antibody heavy or light chain that participates in binding of the antibody to the antigen. The variable region of an antibody can be further divided into hypervariable regions (i.e., complementary determining regions (CDRs)) and relatively conserved regions (i.e., framework regions (FRs)) interposed between the hypervariable regions. In the case of IgG immunoglobulins, the heavy chain variable region or light chain variable region comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, respectively, from N-terminus to C-terminus. In the case of heavy chain antibodies (also referred to herein as nanobodies), for example, heavy chain antibodies from Camelidae, the antigen binding site is composed of a single VH domain (i.e., "VHH" domain). The VHH of a natural heavy chain antibody has a similar structure to the heavy chain variable region of a natural IgG antibody, i.e., comprises four conserved framework regions (FRs) and three complementary determining regions (CDRs).

[0169] "Complementarity determining region" or "CDR region" or "CDR" or "hypervariable region" is a region of an antibody variable domain that is highly variable in sequence and forms structurally defined loops ("hypervariable loops") and / or contains antigen contact residues ("antigen contact points"). CDRs are primarily responsible for binding to antigenic epitopes. The CDRs in the variable domain are typically referred to as CDR1, CDR2, and CDR3 and are numbered sequentially starting from the N-terminus.

[0170] A variety of methods are known in the art for determining CDR sequences within a given VH or VL amino acid sequence: Kabat complementarity determining regions (CDRs) are determined based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Md. (1991)), while Chothia refers to the positions of structural loops (Chothia et al., (1987) J. Mol. Biol. 196: 901-917; Chothia et al. (1989) Nature 342: 877-883). AbM CDRs are a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" CDRs are based on analysis of available complex crystal structures. The residues for each of these CDRs, according to the different CDR determination methods, are described below.

[0171] When referring to antibodies defined by specific CDR sequences defined herein, the scope of said antibodies also encompasses antibodies whose variable region sequences comprise said specific CDR sequences, but whose declared CDR boundaries differ from the specific CDR boundaries defined herein due to the application of a different scheme (e.g., a different assignment system rule or combination).

[0172] The CDRs of the antibodies of the present invention can be manually assessed to determine their boundaries according to any protocol or combination thereof in the art. Unless otherwise indicated, in the present invention, the term "CDR" or "CDR sequence" encompasses CDR sequences determined in any of the above ways.

[0173] "Heavy chain constant region domain" or "heavy chain constant region" refers to a constant region domain from, obtained from, or derived from an immunoglobulin heavy chain, comprising heavy chain constant regions CH1, CH2, CH3, and optionally heavy chain constant region CH4 covalently linked sequentially from N-terminus to C-terminus. In most cases, the heavy chain constant regions CH1 and CH2 are connected by a heavy chain hinge region, but may also be connected by a flexible linker when appropriate.

[0174] The term "EC 50 ”, also known as the “half-maximal effective concentration”, is the concentration of a drug, antibody, or toxic agent that induces a response that is 50% between baseline and maximum after a specified exposure time.

[0175] As used herein, the term "binding" or "specific binding" means that the binding is selective for the antigen and can be distinguished from unwanted or non-specific interactions. The ability of an antigen binding site to bind to a specific antigen can be determined by enzyme-linked immunosorbent assay (ELISA) or conventional binding assays known in the art.

[0176] "Affinity" or "binding affinity" refers to the intrinsic binding ability that reflects the interaction between members of a binding pair. The affinity of a molecule X for its binding partner Y can be expressed by the equilibrium dissociation constant (K D ) indicates that the equilibrium dissociation constant is the dissociation rate constant and the association rate constant (k dis and k on Binding affinity can be measured by common methods known in the art.

[0177] Amino acid mutations can be amino acid substitutions, deletions, insertions, and / or additions. In some embodiments, amino acid mutations are substitutions of one or more amino acids, such as single amino acid substitutions or combinations of multiple amino acid substitutions. Amino acid deletions and insertions include deletions and insertions at the amino and / or carboxyl termini of a polypeptide sequence, as well as deletions and insertions within the polypeptide sequence. Amino acid substitutions of the present invention optionally include conservative amino acid substitutions.

[0178] "Percent (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the specific amino acid sequence set forth in this specification, after aligning the candidate sequence with the specific amino acid sequence set forth in this specification and introducing gaps, if necessary, to achieve the maximum percentage identity, and not considering any conservative substitutions as part of the sequence identity. In some embodiments, the present invention contemplates variants of the antibody molecules of the invention that have a substantial degree of identity, e.g., at least 80%, 85%, 90%, 95%, 97%, 98% or 99% or more, relative to the antibody molecules and sequences thereof specifically disclosed herein. The variants may comprise conservative modifications.

[0179] With respect to polypeptide sequences, "conservative modifications" include substitutions, deletions, or additions to a polypeptide sequence that result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude the polymorphic variants, interspecies homologs, and alleles of the present invention. The following eight groups contain amino acids that are conservative substitutions for each other: 1) Alanine (A), Glycine (G); 2) Aspartic Acid (D), Glutamic Acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine ​​(C), Methionine (M) (see, e.g., Creighton, Proteins (1984)). In some embodiments, the term "conservative sequence modifications" is used to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence.

[0180] The term "therapeutic agent" as used herein encompasses any substance effective in preventing or treating tumors, such as cancer, including chemotherapeutic agents, cytokines, angiogenesis inhibitors, cytotoxic agents, other antibodies, small molecule drugs, or immunomodulators (e.g., immunosuppressants).

[0181] The term "antibody-drug conjugate" or "ADC" refers to an antibody or antibody fragment covalently coupled to a therapeutically active substance or active pharmaceutical ingredient, such that the therapeutically active substance or active pharmaceutical ingredient is targeted to the binding target of the antibody to exhibit its pharmacological function. The therapeutically active substance or active pharmaceutical ingredient may be a cytotoxin that can kill cells (preferably cancer cells) targeted by the ADC. The covalent attachment of the therapeutically active substance, active pharmaceutical ingredient, or cytotoxin may be performed in a non-site-specific manner using a linker, or in a site-specific manner.

[0182] The term "site-specific conjugation" refers to a method of specifically linking a therapeutically active substance or active pharmaceutical ingredient to a specific site of an antibody. In one embodiment, the conjugation is accomplished with the aid of a linker.

[0183] The term "cytotoxic agent" can be used interchangeably with "cytotoxin" and refers to a substance that inhibits or disrupts cellular function and / or causes cell death or destruction. In one embodiment, the cytotoxic agent may include, but is not limited to, bacterial toxins, plant toxins, small molecule toxins, radioactive isotopes, and the like.

[0184] Any antibody-drug conjugate of the present invention can be prepared by conjugating dolastatin and its auristatin derivatives to an antibody. Dolastatin and its auristatin derivatives are important cytotoxins used in antibody-drug conjugates (ADCs), interfering with microtubule dynamics and cell division, and exhibiting anti-tumor and antifungal activity. In one aspect, dolastatin and its auristatin derivatives can be, for example, monomethyl auristatin D (MMAD), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and other auristatins (e.g., the auristatins described in U.S. Publication No. 20130129753).

[0185] Monomethyl auristatin (MMAE), also known as demethyl-auristatin E, is a well-known member of the auristatin compound family. Its structural formula is as follows:

[0186] MMAE is conjugated to a monoclonal antibody via a linker to form an ADC. Generally speaking, the linker is cleaved after the ADC enters tumor cells, releasing MMAE, which then exerts its cytotoxic effect and kills tumor cells.

[0187] DXD, a derivative of Exatecan, is an effective DNA topoisomerase I inhibitor and has been widely used in the field of ADCs. It is linked to the cysteine ​​residues on the antibody via a cleavable tetrapeptide linker (GGFG) with the help of maleimide. Currently, Deruxtecan, consisting of maleimide-GGFG-DXD, is commercially available as an ADC drug linker and has the following structure:

[0188] The terms "linker" and "connector" are used interchangeably herein to refer to a chemical moiety that covalently links an antibody to a therapeutically active substance or active pharmaceutical ingredient in an ADC. In one embodiment, the linker may comprise amino acid residues that connect the antigen to the payload. The amino acid residues may form a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide, or dodecapeptide unit. The amino acid residues include naturally occurring amino acid analogs such as citrulline or β-amino acids, such as β-alanine, or ω-amino acids such as 4-amino-butyric acid.

[0189] According to the property classification, the linkers suitable for the present invention can be protease-degradable linkers, non-cleavable linkers, acid-sensitive linkers, silicone-structured linkers, disulfide-carbamate linkers, MC-GGFG linkers, TRX linkers, galactoside-containing linkers, pyrophosphate linkers, near-infrared-sensitive linkers, UV-sensitive linkers, etc.

[0190] The linker of the present invention can also be a combination of one or more linkers. For example, a cathepsin-degradable linker can be combined with other types of linkers to form a new linker. Therefore, the "linker" described in the present invention encompasses a single type of linker or a combination of different types of linkers, as long as it is capable of conjugating the antibody of the present invention to the drug.

[0191] The term "load" or "drug load" or "payable load" refers to the average number of therapeutically active substances or active pharmaceutical ingredients per antibody within the ADC molecule ("payable load" is used interchangeably herein with "therapeutically active substance or active pharmaceutical ingredient"). Drug load can range from 1-20 therapeutically active substances or active pharmaceutical ingredients per antibody.

[0192] The term "drug / antibody ratio" or "DAR" refers to the ratio of the therapeutically active substance or active pharmaceutical ingredient (D) coupled to the antibody to the antibody. The ADCs described herein typically have a DAR of 1-8, and in certain embodiments have a DAR of 1-8, 2-8, 2-6, 2-5, 3-8, 4-6, and 2-4. Representative DAR values ​​are, for example, 1, 2, 3, 4, 5, 6, 7, 8, typically expressed as the letter D or a combination of DAR and a number, wherein the number represents the numerical value of the DAR, for example, D2 / DAR2 represents a drug / antibody ratio with a DAR value of 2. In some embodiments, the DAR is the average DAR, i.e., the overall ratio of the small molecule drug moiety (D) coupled to the Ab moiety described herein to the Ab moiety in the product as measured by a detection method (e.g., by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assay, electrophoresis, and / or HPLC).

[0193] The DAR may be limited by the number of attachment sites on the antibody. For example, where the attachment site is a cysteine ​​thiol, the antibody may have only one or a few cysteine ​​thiol groups or may have only one or a few sufficiently reactive thiol groups through which the linker unit can be attached.

[0194] In some embodiments, the average DAR value of the conjugates of the invention is from 0 to 8, e.g., 3.0-4.0, 4.0-5.0, 7.0-8.0, e.g., a range having two of these values ​​as endpoints.

[0195] The terms "individual" or "subject" are used interchangeably and refer to mammals. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In particular, the individual is a human.

[0196] The term "treatment" refers to a clinical intervention intended to alter the natural course of a disease in the individual being treated. Desired therapeutic effects include, but are not limited to, preventing the onset or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating the disease state, and alleviating or improving prognosis. In some embodiments, the antibody molecules of the present invention are used to delay the development of the disease or to slow the progression of the disease.

[0197] The term "effective amount" refers to an amount or dosage of an antibody or composition of the present invention that produces the desired effect in a patient in need of treatment or prevention after administration to the patient in a single or multiple doses. The effective amount can be readily determined by the attending physician, who is skilled in the art, by considering a variety of factors such as the species of the mammal; weight, age, and general health; the specific disease involved; the extent or severity of the disease; the response of the individual patient; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and the use of any concomitant therapy.

[0198] The term "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the desired dosage and for the desired period of time. The therapeutically effective amount of an antibody or antibody fragment or conjugate or composition thereof can vary depending on a variety of factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit the desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the antibody or antibody fragment or conjugate or composition are outweighed by the therapeutically beneficial effects. A "therapeutically effective amount" preferably inhibits a measurable parameter (e.g., tumor growth rate, tumor volume, etc.) by at least about 20%, more preferably at least about 40%, even more preferably at least about 50%, 60%, or 70%, and still more preferably at least about 80% or 90% relative to an untreated subject. The ability of a compound to inhibit a measurable parameter (e.g., cancer) can be evaluated in an animal model system that is predictive of efficacy in human tumors.

[0199] The term "pharmaceutical composition" refers to a composition that is in form permitting the biological activity of the active ingredient contained therein to be effective, and that contains no additional ingredients that are unacceptably toxic to a subject to which the composition would be administered.

[0200] II. Compositions of the Invention

[0201] In some embodiments, the present invention provides a composition comprising any of the anti-FOLR1 antibodies described herein, or ADC molecules thereof, preferably a pharmaceutical composition. In one embodiment, the composition further comprises a pharmaceutical excipient, such as a pharmaceutical carrier or a pharmaceutical excipient known in the art. In one embodiment, the composition (e.g., a pharmaceutical composition) comprises an anti-FOLR1 antibody of the present invention, or ADC molecules thereof, and a combination of one or more other therapeutic agents.

[0202] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0203] For the use of pharmaceutical excipients and their applications, see also "Handbook of Pharmaceutical Excipients", 8th edition, RC Rowe, PJ Eskey and S C Owen, Pharmaceutical Press, London, Chicago.

[0204] The compositions of the present invention can be in a variety of forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as powders or suspensions, liquid solutions (e.g., injectable solutions and infusible solutions), liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic use.

[0205] The administration route of the composition of the present invention is according to known methods, for example, oral, intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes; by sustained release system or by implant device. In certain embodiments, the composition can be administered by bolus injection or by continuous infusion or by implant device.

[0206] The subject can be a mammal, e.g., a primate, e.g., a human (e.g., an individual suffering from a disease described herein or at risk of suffering from a disease described herein). In one embodiment, the subject suffers from a disease described herein (e.g., cancer) or is at risk of suffering from a disease described herein. In certain embodiments, the subject receives or has received other treatments, e.g., chemotherapy and / or radiation therapy. In some embodiments, the subject has previously received or is currently receiving immunotherapy.

[0207] A medicament comprising the antibody described herein can be prepared by mixing an anti-FOLR1 antibody of the present invention, or an ADC molecule thereof, having a desired degree of purity with one or more optional pharmaceutical excipients, preferably in the form of a lyophilized formulation or an aqueous solution.

[0208] The pharmaceutical composition or preparation of the present invention may also include more than one active ingredient, which is required for the specific indication being treated, preferably having those active ingredients of complementary activities that do not adversely affect each other. For example, it is desirable to also provide other therapeutic agents, including chemotherapeutics, angiogenesis inhibitors, cytokines, cytotoxic agents, other antibodies, small molecule drugs or immunomodulators (such as immune checkpoint inhibitors or agonists). The active ingredient is suitably combined in an amount effective for the purpose.

[0209] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, eg, films, or microcapsules.

[0210] III. Preparation of Antibodies and Antibody-Drug Conjugates of the Invention

[0211] In one embodiment, the present invention provides a method for producing an anti-FOLR1 antibody, wherein the method comprises culturing a host cell comprising a nucleic acid encoding an anti-FOLR1 antibody or an expression vector comprising the nucleic acid under conditions suitable for expression of the nucleic acid encoding the anti-FOLR1 antibody, and optionally isolating the anti-FOLR1 antibody. In a certain embodiment, the method further comprises recovering the anti-FOLR1 antibody from the host cell (or host cell culture medium).

[0212] To recombinantly produce an anti-FOLR1 antibody of the invention, nucleic acid encoding an anti-FOLR1 antibody of the invention is first isolated and inserted into a vector for further cloning and / or expression in a host cell. Such nucleic acid is readily isolated and sequenced using conventional procedures, for example, by using oligonucleotide probes that are capable of specifically binding to a nucleic acid encoding an anti-FOLR1 antibody of the invention.

[0213] The anti-FOLR1 antibodies of the present invention, prepared as described herein, can be purified by known techniques such as high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography, size exclusion chromatography, and the like. The actual conditions used to purify a particular protein will also depend on factors such as net charge, hydrophobicity, and hydrophilicity, and will be apparent to those skilled in the art. The purity of the anti-FOLR1 antibodies of the present invention can be determined by any of a variety of well-known analytical methods, including size exclusion chromatography, gel electrophoresis, high performance liquid chromatography, and the like.

[0214] The generation of antibody-drug conjugates can be accomplished by any technology known to those skilled in the art. In some aspects, the coupling of drug-linker and antibody is accomplished by reacting with the amino acid residues of the antibody. In some embodiments, a heteroaryl linker L with a leaving group is used to couple drug D to the cysteine ​​residues of the antibody to prepare a conjugate of Formula I of the present invention. In some embodiments, the conditions under which the antibody is treated with a reducing agent such as tris(2-hydroxyethyl)phosphine (TCEP) can be controlled to destroy the interchain disulfide bonds of the antibody and expose free sulfhydryl groups for coupling with heteroaryl linker-drug. For IgG1 type antibodies, up to four linked disulfide bonds can be reduced, thereby generating up to 8 reactive sulfhydryl groups for coupling. The conjugate prepared by this method can contain zero, one, two, three, four, five, six, seven or eight drugs in each antibody molecule.

[0215] When the prepared conjugate is a composition having different drug conjugation sites and / or numbers of conjugates, the drug loading of the conjugate is represented by the average DAR, which is the average number of drug molecules per antibody. The average number of drug per antibody of the prepared antibody-drug conjugate composition can be characterized by conventional means, such as mass spectrometry, ELISA assay, and HPLC. In other embodiments, the quantitative distribution of the antibody-drug conjugate, represented by n, can also be determined. Homogeneous antibody-drug conjugates where n is a certain value can be separated, purified, and characterized from antibody-drug conjugates having different drug loadings by means such as reversed-phase HPLC or electrophoresis. Example

[0216] The present invention is further illustrated by the following examples; however, it should be understood that the examples are described in an illustrative rather than a limiting sense and that various modifications may be made by those skilled in the art.

[0217] Unless expressly stated to the contrary, the practice of the present invention will employ conventional methods of chemistry, biochemistry, organic chemistry, molecular biology, microbiology, recombinant DNA technology, genetics, immunology, and cell biology within the art. The experimental methods described, unless otherwise specified, are conventional methods in the art using default parameters, steps, and the like; the experimental materials used, unless otherwise specified, are commercially available products. For examples in which specific techniques or conditions are not specified, the techniques or conditions described in the literature within the art or in accordance with the corresponding product instructions were used. For reagents or instruments used for which the manufacturer is not specified, all are conventional products that can be purchased through regular channels.

[0218] Example 1. Preparation of mouse hybridomas producing anti-human FOLR1 antibodies

[0219] In this example, mice were immunized with FOLR1 protein, fused with SP2 / 0 cells, and positive clones were screened by flow cytometry. The specific method is as follows:

[0220] Animal Immunization: Balb / c female mice were immunized with 1 mg / mL FOLR1-Fc protein (FO1-H5253, Acro) as the immunogen (10 μg / mouse) mixed with an equal volume of Gerbu MM (Gerbu, 3001). Immunizations were performed four times, with each immunization taking place four days apart. Spleens were harvested and fused two days after the final immunization.

[0221] FOLR1-Fc protein was used as the immunogen. The antigen was diluted to 1 mg / ml and mixed with an equal volume of CFA (Sigma, F5881) or IFA (Sigma, F5506) (CFA was used for the initial immunization and IFA was used for subsequent immunizations). Balb / c female mice were immunized with protein. The initial immunization was 50 μg / mouse and the subsequent immunizations were 25 μg / mouse. Immunizations were repeated for more than 3 times at intervals of 2 weeks. 14 days after the last immunization, FOLR1 protein was injected intraperitoneally for shock immunization. Three days later, the mouse spleens were harvested for cell fusion.

[0222] Cell fusion: Mouse spleen cells and SP2 / 0 cells (ATCC No. CRL-1581) were electrofused at a ratio of 2:1 (BTX electrofusion instrument: ECM2001 + ), cultured in 96-well culture plates with HAT medium (Sigma-Aldrich, catalog number: H0262), and hybridoma cell supernatant antibody screening was performed after 10 days.

[0223] Screening for hybridoma-positive clones: Collect the cultured cell supernatant and perform an ELISA or FACS binding assay. Select the positive wells in the cell culture supernatant and culture them in 96-well culture plates using HT medium (Sigma-Aldrich, Catalog No. H0137). After 7-10 days, visible clones will appear, and the supernatant will be collected for antibody detection. Observe under an inverted microscope and select the positive wells with only a single clone. Expand the culture and freeze. After culturing in serum-free medium (SFM, Thermo, 12045076), collect the supernatant and purify it for subsequent testing.

[0224] ELISA binding assay: 50 μL of hybridoma supernatant, positive control, and negative control were added to a 96-well flat-bottom assay plate (Corning, 9018) coated with human FOLR1 protein (hFOLR1-his, Acro, FO1-H52H1) or cynomolgus macaque FOLR1 protein (cynoFOLR1-his, Acro, FO1-C52H8). The plates were incubated at 37°C for 60 minutes, washed three times with PBST, and then the secondary antibody (Anti-Mouse IgG, Sigma, A0168) was added and incubated at 37°C for 30 minutes. After washing three times with PBST, 100 μL of TMB (Inc. Biotech, EL0009) was added to each well. After 15 minutes of color development, the reaction was terminated by adding 50 μL of sulfuric acid to each well. OD values ​​were read on a microplate reader. The results are shown in Table 1.

[0225] FACS binding assay: CHOK1 cells expressing human FOLR1 (CHOK1-hFOLR1, Kangyuan Bochuang, KC-1236), ovarian cancer cells SK-OV-3 (Kebai, CBP60291), human oral epithelial cancer cells KB (Kebai, CBP60259), and CHOK1 cells expressing cynomolgus macaque FOLR1 (CHOK1-cyno FOLR1, Kangyuan Bochuang, KC-1238) were added to a 96-well plate (Corning, 3799). Hybridoma supernatant, positive control, and negative control were then added to the 96-well plate containing the four cells and incubated at 4°C for approximately 1 hour. The cells were washed three times with FACS buffer, and 100 μL of secondary antibody (Invitrogen, B118301) was added to each well to resuspend the cells and incubate at 4°C for approximately 1 hour. After washing three times with FACS buffer, 100 μL FACS buffer was added to each well to resuspend the cells and the cells were analyzed by flow cytometry (BECKMAN COULTER cytoFLEX or BD FACSCelesta TM) were used to read the mean fluorescence intensity (MFI), and the results are shown in Table 1. A total of four positive hybridoma clones were screened: 115E3C9, 148B9H3, 182C2D11, and 186D9A7.

[0226] Table 1 The ability of the supernatants of positive hybridoma clones to bind to hFOLR1 and cynoFOLR1 proteins Note: * The ELISA assay used mouse antibody serum after immunization but before cell fusion, and the FACS assay used 1 μg / mL Farletuzumab-mIgG (Farletuzumab variable region sequence constructed on the mouse constant region). #The ELISA assay used HAT medium, and the FACS assay used FACS buffer.

[0227] Example 2. Preparation and identification of mouse monoclonal antibodies against human FOLR1

[0228] The hybridoma cells listed in Table 1 were cultured in serum-free medium for 10 days. The supernatant was collected and the mouse monoclonal antibody was purified using a Protein A column (Borgron (Shanghai) Biotechnology Co., Ltd., Catalog No. AA0272). The binding activity and ADC cytotoxicity of the anti-human FOLR1 antibody were determined by flow cytometry.

[0229] 1. Binding activity of anti-human FOLR1 antibodies to human ovarian cancer cells SK-OV-3, human oral epithelial cancer cells KB, and engineered cell lines expressing human and cynomolgus monkey FOLR1 (CHOK1-hFOLR1 and CHOK1-cynoFOLR1)

[0230] Human FOLR1-expressing CHOK1 cell line (CHOK1-hFOLR1, Kangyuan Bochuang KC-1236), SK-OV-3 cells (Kebai, CBP60291), KB cells (Kebai, CBP60259), or cynomolgus macaque FOLR1-expressing CHOK1 cell line (CHOK1-cyno FOLR1, Kangyuan Bochuang, KC-1238) were plated at 100 μL / well into a 96-well U-bottom plate and centrifuged. The supernatant was discarded. 100 μL of serial dilutions of antibody diluted in FACS buffer (PBS containing 1% FBS) was added to each well and incubated at 4°C for approximately 1 hour. The cells were washed three times with FACS buffer, and 100 μL of secondary antibody (Invitrogen, Cat. No. B118301) diluted in FACS buffer was added to each well and incubated at 4°C for approximately 1 hour. The cells were washed three times with FACS buffer, and 100 μL of FACS buffer was added to each well to resuspend the cells. The MFI was read by flow cytometry and analyzed using Graphpad Prism 8.0 software. The logarithm of the antibody concentration was used as the x-axis and the corresponding MFI value was used as the y-axis. A four-parameter regression model was used to fit the antibody dose-effect curve and calculate the EC. 50 , the results are shown in Table 2.

[0231] As shown in Table 2, the anti-FOLR1 antibody clones 115E3C9, 148B9H3, 182C2D11, and 186D9A7 all had strong binding activity to human ovarian cancer cells SK-OV-3, human oral epithelial cancer cells KB, and engineered cell lines expressing human and cynomolgus monkey FOLR1 (CHOK1-hFOLR1 and CHOK1-cynoFOLR1), and their activities were similar to or better than those of Farletuzumab-mIgG.

[0232] Table 2 Binding activity of anti-FOLR1 antibodies to cells expressing human and cynomolgus monkey FOLR1. N / A

[0233] 2. Cytotoxicity Induced by αMFc-CL-MMAE and Anti-human FOLR1 Antibody

[0234] αMFc-CL-MMAE (Moradec, AM-202AE-50) is an anti-mouse IgG Fc-specific antibody conjugated to MMAE via a cleavable linker. αMFc-CL-MMAE recognizes the Fc terminus of the anti-human FOLR1 mouse antibody, leading to endocytosis and intracellular release of MMAE in FOLR1-expressing cells, which kills the cells. KB cells were obtained by trypsinization and centrifuged to adjust the cell density to 4×10 4cells / mL. Add 25 μL of antibody concentration gradient dilution diluted in culture medium (starting and ending concentration is 20 nM, 4-fold dilution) and 50 μL of cell suspension to each well of a white bottom transparent 96-well plate. After incubation for 10 minutes, add 25 μL of αMFc-CL-MMAE working solution (Moradec, AM-202AE-50) prepared with culture medium to each well, and place the 96-well plate in an incubator at 37 ° C and 5% culture. After 3 days, add 50 μL of CTG (Adamas Life, RA-GL11-A) to each well, read the fluorescence relative light unit with a microplate reader, and fit the RLU using a four-parameter model to calculate the EC of each antibody. 50 The results are shown in Table 3. Anti-FOLR1 antibody clones 115E3C9, 148B9H3, 182C2D11, and 186D9A7 all resulted in strong killing activity, which was similar to or better than that of Farletuzumab-mIgG.

[0235] Table 3. Cytotoxicity induced by αMFc-CL-MMAE and anti-human FOLR1 antibody N / A: No binding activity or poor binding activity, no effective EC 50 value.

[0236] Example 3. Anti-FOLR1 Antibody Sequencing and Preparation of Chimeric Antibodies and Their Functional Identification

[0237] 1. Sequencing, Expression, and Purification of Anti-FOLR1 Antibodies

[0238] The positive hybridoma clones were sequenced, and the sequences are shown in Table 4. The sequenced light and heavy chain variable regions (Table 4) were constructed onto human constant regions (IgG1 / κ, Table 5) to construct the corresponding chimeric antibodies, and the sequences were verified by sequencing. Chimeric antibodies are named by appending the prefix "ch" to the corresponding hybridoma clone number. For example, the chimeric antibody obtained in this example using hybridoma clone 115E3C9 was named ch115E3C9 and used for in vitro functional characterization and in vivo efficacy studies.

[0239] The corresponding nucleic acid encoding the antibody was transfected into Expi293 cells for antibody expression and purified using a Protein A column as follows:

[0240] 1.5×10 6 Cells / mL of Expi293 cells were cultured in a shaker at 120 rpm at 37°C and 8% CO2. The cell density and viability were measured the next day. The density should be around 3×10 6cells / mL, with a viability greater than 95%. Use OPM-293CD05 Medium (OPM, Cat. No. 81075-001) to dilute the plasmid containing the encoding nucleic acid to a total volume of 1 μg / mL. The volume of the culture medium used to dilute the plasmid is 1 / 20 of the transfection volume, and the ratio of light chain to heavy chain is 1:1.

[0241] 1.5. Mix PEI (1 mg / mL, Polysciences, Catalog No. 24765-1) by inversion and dilute with OPM-293CD05 Medium at 1 / 20 the transfection volume. Incubate at room temperature for 5 minutes. Add the diluted PEI to the diluted plasmid and mix thoroughly. Incubate at room temperature for 15 minutes. Add the PEI / plasmid complex to a shake flask containing Expi293 cells and culture at 37°C, 8% CO2, and 120 rpm for 24 hours. Then, add 10% OPM-293 ProFeed (OPM, Catalog No. F081918) and continue culturing for 5-7 days. Collect the supernatant.

[0242] Place the gasket at the bottom of the gravity chromatography column and press it tightly. The volume of the filler Protein A (Cytiva, product number: 17549801) suspension = target filler volume / filler suspension ratio. Vortex the filler thoroughly and add it to the bottom of the gravity chromatography column. Add PBS until the outlet pH reaches the target pH. Add the sample to the chromatography column, add at least 10 column volumes (CV) of elution buffer, add 5CV of elution buffer (20mM NaAc, pH3.0), incubate for 3-5 minutes, and collect the eluate. Adjust the pH to 7.2 with neutralization buffer (1M Tris), determine the protein concentration using Nanodrop, and exchange the solution with PBS using a Millipore ultrafiltration centrifuge tube (50kDa).

[0243] Table 4. CDR sequences and variable region sequences of anti-FOLR1 hybridoma antibodies (determined according to the Kabat protocol)

[0244] Table 5 Chimeric antibody and humanized antibody constant region sequences

[0245] 2. Binding activity of anti-FOLR1 chimeric antibodies to human ovarian cancer cells SK-OV-3, human oral epithelial cancer cells KB, and engineered cell lines expressing human and cynomolgus macaque FOLR1 (CHOK1-hFOLR1 and CHOK1-cynoFOLR1)

[0246] Human ovarian cancer cells SK-OV-3, human oral epithelial cancer cells KB, and engineered cell lines expressing human and crab-eating macaque FOLR1 (CHOK1-hFOLR1 and CHOK1-cynoFOLR1) were added to 96-well U-bottom plates at 100 μL per well, centrifuged, and the supernatant was discarded. 100 μL of FACS buffer (PBS solution containing 1% FBS) prepared with gradient dilutions of antibody concentrations was added to each well and incubated at 4°C for about 1 hour. Wash three times with FACS buffer, add 100 μL of secondary antibody diluted in FACS buffer (Invitrogen, catalog number: A21445) to each well, and incubate at 4°C for about 1 hour. Wash three times with FACS buffer, add 100 μL of FACS buffer to each well to resuspend the cells. The MFI was read by flow cytometer, and the data was analyzed using Graphpad Prism 8.0 software. The logarithm of the antibody concentration was used as the x-axis, and the corresponding MFI value was used as the y-axis. A four-parameter regression model was selected to fit the antibody dose-effect curve, and the EC was calculated. 50 .

[0247] The results are shown in Table 6. The chimeric antibodies ch115E3C9, ch148B9H3, ch186D9A7 and ch182C2D11 have strong binding activity with human ovarian cancer cells SK-OV-3, human oral epithelial cancer cells KB and engineered cell lines expressing human and cynomolgus monkey FOLR1 (CHOK1-hFOLR1 and CHOK1-cynoFOLR1), which are comparable to or better than Farletuzumab.

[0248] Table 6 Binding activity of anti-FOLR1 chimeric antibodies to human FOLR1 and cynomolgus monkey FOLR1 (EC 50 ,nM) N / A: No binding activity or poor binding activity, no effective EC 50 NT: Not tested.

[0249] 3. Cytotoxicity of anti-human FOLR1 chimeric antibody conjugate with MMAE

[0250] 3.1 Preparation of anti-FOLR1 antibody-MMAE conjugates

[0251] Antibodies ch115E3C9, ch148B9H3, ch182C2D11, ch186D9A7, or the control antibody Farletuzumab were added to PBS buffer to a concentration of approximately 1 mg / mL. EDTA solution (Shanghai Trial, 10009617) was added to a concentration of approximately 2 mM. 1 M Tris-salt solution was added to adjust the reaction system to a pH between 6.6 and 7.5. 2-6 equivalents of TCEP (Thermo, 20490) were added for reduction, and the mixture was gently shaken on a homogenizer at 37°C for 1-3 hours. The homogenizer temperature was then adjusted to approximately 4°C, the reaction mixture cooled, and 5-10 equivalents of DMSO-dissolved VcMMAE (MCE, HY-15575, Figure 1) was added. The reaction mixture was allowed to react at 4°C for 1-2 hours. Finally, the reaction mixture was transferred to a 30K ultrafiltration tube and the buffer was exchanged 6-8 times with 10 mM histidine-HCl solution, pH 6.0. The product was concentrated to an appropriate volume, added to a equilibrated desalting column, and centrifuged to obtain the purified ADC product. The concentration was determined using a Nanodrop analyzer, and the DAR value was determined using hydrophobic liquid chromatography. The resulting FOLR1 antibody-MMAE conjugates were ch115E3C9-MMAE, ch148B9H3-MMAE, ch182C2D11-MMAE, ch186D9A7-MMAE, and Farletuzumab-MMAE. The structures of the FOLR1 antibody-MMAE conjugates are shown in Figure 1.

[0252] 3.2 Cytotoxicity assay of the conjugate of anti-FOLR1 antibody and MMAE

[0253] Adjust the KB cell concentration to 4 × 10 4 Cells / mL, 50 μL / well were inoculated in a white bottom transparent 96-well plate. 50 μL of ADC concentration gradient dilution prepared with MEM complete medium was added to each well and cultured in a 37 ° C, 5% CO2 incubator. After 3 days, the number of living cells and cell viability were quantified by CTG method. Specifically, 50 μL of CTG reagent (Damas Life, RA-GL11) was added to each well, reacted in the dark at room temperature for 5 minutes, and the relative light unit (RLU) was read with a microplate reader. Graphpad Prism 8.0 software was used to analyze the experimental data, with the logarithm of the antibody concentration as the x-axis and the corresponding RLU value as the y-axis. A four-parameter regression model was selected to fit the dose-effect curve of the antibody. The results are shown in Figure 2 and Table 7. ch115E3C9-MMAE, ch148B9H3-MMAE, ch182C2D11-MMAE, and ch186D9A7-MMAE have strong cell-killing toxicity, which is similar to or better than that of Farletuzumab-MMAE.

[0254] Table 7. Cytotoxicity of anti-FOLR1 chimeric antibody MMAE conjugates N / A: Not applicable.

[0255] Example 4. Humanization of anti-FOLR1 antibodies and expression and purification of humanized antibodies

[0256] Using Kabat numbering to identify CDRs, the human germline gene with the highest homology to the mouse sequence was selected as the acceptor framework, and the mouse CDRs were transplanted into the human framework. Based on the importance of amino acids, backmutations were performed, remutating key amino acids in the transplanted framework region to their corresponding mouse counterparts. Several variants were designed for each heavy and light chain.

[0257] 1. Humanization of anti-FOLR1 antibody 115E3C9

[0258] The HCDR and LCDR of the 115E3C9 mouse antibody were transplanted onto the human germline genes IGHV7-4-1*01 and IGKV1-39*01, respectively. The resulting sequences are as follows:

[0259] Table 8. The humanized sequence of anti-FOLR1 antibody 115E3C9 is as follows

[0260] 2. Humanization of anti-FOLR1 antibody 148B9H3

[0261] The HCDR and LCDR of the 148B9H3 mouse antibody were transplanted onto the human germline genes IGHV1-3*01 and IGKV1-33*01, respectively. The resulting sequences are as follows:

[0262] Table 9. The humanized sequence of anti-FOLR1 antibody 148B9H3 is as follows

[0263] 3. Humanization of anti-FOLR1 antibody 186D9A7

[0264] The HCDR and LCDR of the 186D9A7 mouse antibody were transplanted into the human germline genes IGHV1-69, KV1-NL1, and IGKV1-5, respectively, to obtain the following humanized sequences.

[0265] Table 10. The humanized sequence of anti-FOLR1 antibody 186D9A7 is as follows

[0266] 4. Humanization of anti-FOLR1 antibody 182C2D11

[0267] The HCDRs and LCDRs of the 182C2D11 murine antibody were transplanted onto the human germline genes IGHV1-69, KV1-NL1, and IGKV1-5, respectively. The resulting heavy chain variable region sequences are shown in Table 11 below. The corresponding light chain variable region sequences obtained are consistent with the light chain variable region sequences of the humanized 186D9A7 antibody, i.e., the obtained light chain variable region sequences of the 182C2D11 humanized antibody are shown in one of SEQ ID NOs: 55-60. The specific heavy and light chain variable region sequence combinations of the 182C2D11 humanized antibody are shown in Table 12.

[0268] Table 11. Humanized heavy chain variable region sequences of anti-FOLR1 antibody 182C2D11

[0269] Table 12. Heavy chain variable region sequences and light chain variable region sequences corresponding to the constructed humanized antibodies

[0270] 5. Expression and Purification of Humanized Anti-FOLR1 Antibody

[0271] The light and heavy chain variable regions of the humanized antibodies listed in Tables 8-11 were constructed onto human constant regions (hIgG1 / κ, Table 5) according to the combinations listed in Table 12. Gene synthesis was performed and sequencing confirmed consistency with the designed sequences. Expression was performed in Expi293 cells using the method described in Example 3 and purification was performed using a Protein A column.

[0272] Example 5. Functional characterization of anti-FOLR1 humanized antibodies

[0273] The humanized antibodies were tested for their binding activities to human FOLR1 (SK-OV-3, KB), mouse and cynomolgus monkey FOLR1 (CHOK1-cynoFOLR1), human FOLR2, human FORL3 and human FOLR4, and their ability to block the binding of FOLR1 and Folic acid-BSA conjugate (FA-BSA).

[0274] 1. Saturation Binding Experiment of Humanized Anti-FOLR1 Antibody

[0275] The binding activity of the humanized anti-FOLR1 antibodies to human FOLR1, mouse FOLR1, and cynomolgus monkey FOLR1 was tested using the method disclosed in Example 3. The results of antibody binding to human and cynomolgus monkey FOLR1 are shown in Table 13. The results of antibody binding to mouse FOLR1 are shown in Figure 3D , where, with the exception of hz115E3C9-H7L2, all other humanized anti-FOLR1 antibodies tested showed no significant binding to mouse FOLR1.

[0276] Table 13. EC values ​​of humanized anti-FOLR1 antibodies binding to human FOLR1 and cynomolgus monkey FOLR1 50 . NT: not tested; N / A: not applicable.

[0277] 2. Binding activity of anti-FOLR1 humanized antibodies to human FOLR2, human FOLR3, and human FOLR4

[0278] The nonspecific binding activity of the anti-human FOLR1 humanized antibody to human FOLR2, human FOLR3, and human FOLR4 (IZUMO1) was determined by enzyme-linked immunosorbent assay (ELISA). High-adsorption 96-well microtiter plates were coated with human FOLR2 protein (Acro, FO2-H5223), human FOLR3 protein (Acro, FO3-H52H3), and human FOLR4 / IZUMO1 protein (Acro, FO4-H52H3). Positive controls, biotin-FOLR2, biotin-FOLR3, and biotin-FOLR4, were coated with FA-BSA (cusabio, CSB-MC00271b0105) in high-adsorption 96-well microtiter plates overnight at 4°C. The next day, the wells were blocked with 1% BSA-PBS blocking buffer at 37°C for 1 hour. 100 μL of serial dilutions of the antibody or biotin-conjugated FOLR2, FOLR3, or FOLR4 in 1% BSA-PBST was added to each well and incubated at 37°C for 1 hour. After three washes with 0.05% PBST, 100 μL of secondary antibodies (Sigma, A8667 and BD, 554066) in 1% BSA-PBST was added to each well. SA-HRP was used for the positive control, while anti-human IgG HRP was used for the other test antibodies. The wells were incubated at 37°C for 1 hour. After three washes with PBST, TMB color development (BD, 555214) was performed. After stopping with stop solution (Solarbio, C1058), absorbance at 450 nm and 630 nm was measured using a microplate reader. OD450-OD630 values ​​were fitted using a four-parameter model.

[0279] As shown in Figures 3A to 3C, all anti-FOLR1 humanized antibodies tested had no significant non-specific binding to FOLR2, FORL3, and human FOLR4.

[0280] 3. Blocking Experiment of Anti-FOLR1 Humanized Antibody on the Binding of FA-BSA and FOLR1

[0281] A high-adsorption 96-well microtiter plate was coated with FA-BSA protein overnight at 4°C. The next day, the plate was blocked with 1% BSA-PBS at 37°C for 1 hour. A 1:1 mixture of FA-BSA serial dilutions or antibody serial dilutions diluted in 1% BSA-PBST was added to the biotin-labeled FOLR1 protein. 100 μL of the antibody-protein mixture was added to the blocked 96-well microtiter plate and incubated at 37°C for 1 hour. After washing four times with PBST, 100 μL of Strep-HRP (BD, 554066, 1:5000) was added to each well and incubated at 37°C for 1 hour. After washing four times with PBST, TMB was used for color development. After termination, the absorbance at 450 nm and 630 nm was measured using a microtiter plate reader. The OD450-OD630 values ​​were calculated and fitted using a four-parameter model. As shown in Figure 4, none of the detection antibodies blocked the binding of FA-BSA to FOLR1.

[0282] 4. Cytotoxicity Induced by αHFc-CL-MMAE and Humanized Anti-FOLR1 Antibody

[0283] αHFc-CL-MMAE (Moradec, AH-102-AE) is an anti-human IgG Fc-specific antibody conjugated to MMAE via a cleavable linker. αHFc-CL-MMAE recognizes the Fc terminus of anti-human FOLR1 chimeric or humanized antibodies, leading to endocytosis and intracellular release of MMAE in cells expressing FOLR1, killing the cells. KB cells or SK-OV-3 cells were obtained by trypsinization and the cell density was adjusted to 4×10 4 cells / mL, add 25 μL of antibody concentration gradient dilutions prepared in culture medium and 50 μL of cell suspension to each well of a white bottom 96-well plate. After incubation for 10 minutes, add 25 μL of αHFc-CL-MMAE working solution (Moradec, AH-202AE-50) prepared in culture medium to each well. Place the 96-well plate in a cell culture incubator at 37°C and 5% culture for 3 to 7 days. Add 50 μL of CTG to each well, read the relative light unit (RLU) value with a microplate reader, and use a four-parameter model to fit the RLU to calculate the EC value of each antibody. 50The results are shown in Table 14. All the humanized anti-FOLR1 antibodies tested had strong cytotoxic activity against KB and / or SK-OV-3 cells, which was comparable to or better than that of Farletuzumab.

[0284] Table 14. Cytotoxicity induced by αHFc-CL-MMAE and anti-FOLR1 humanized antibodies. NT: Not tested; N / A: No binding activity or poor binding activity, no effective EC 50 value.

[0285] Example 6. Preparation of a conjugate of anti-human FOLR1 humanized antibody and MMAE

[0286] The conjugate of anti-human FOLR1 humanized antibody and MMAE was prepared by the method described in Section 3.1 of Example 3. The conjugate (antibody ADC) was named according to the name of the corresponding antibody, and its concentration and DAR value were tested, and its biological activity was further tested.

[0287] 6.1 Cytotoxicity Assay of Anti-Human FOLR1 Humanized Antibody ADC

[0288] KB cells or SK-OV-3 cells were obtained by trypsinization and the cell concentration was adjusted to 4 × 10 4 cells / mL, 50 μL / well were inoculated in a white bottom transparent 96-well plate. 50 μL of the antibody concentration gradient diluted in the culture medium was added to each well of the 96-well plate, and the 96-well plate was placed in a 37°C, 5% CO2 incubator for 3 days. 50 μL of CTG reagent was added to each well, incubated in the dark at room temperature for 5 minutes, and the relative light unit value was read with a microplate reader. The experimental data were analyzed using Graphpad Prism 8.0 software, with the logarithm of the antibody concentration as the x-axis and the corresponding RLU value as the y-axis. A four-parameter regression model was selected to fit the dose-effect curve of the antibody. The results are shown in Figure 5 and Table 15. All ADCs of the tested antibodies have strong SK-OV-3 cell killing activity and KB cell killing activity, and their activity is comparable to or better than that of the control Farletuzumab-MMAE.

[0289] Table 15 Cytotoxicity of anti-FOLR1 humanized antibody MMAE conjugates N / A: No binding activity or poor binding activity, no effective EC 50 value.

[0290] Example 7. Anti-human FOLR1 antibody ADC inhibits tumor growth in a mouse model

[0291] 7.1 Preparation of anti-human FOLR1 antibody and DXD conjugate

[0292] Antibody was added to PBS buffer to a reaction concentration of 1.0 mg / mL. 500 mM EDTA (Shanghai Trial, 10009617) was added to a final EDTA concentration of 2 mM. TCEP solution (Thermo, 20490) was added to the reaction solution and mixed thoroughly (molar ratio of TCEP:mAb = 6:1). The reaction was incubated at 37°C and 600 rpm for 2 hours to reduce the interchain disulfide bonds of the antibody. After the reaction was complete, the reaction solution was cooled to 4°C. Deruxtecan solution (MCE, HY-1363E) dissolved in DMSO was added to the reaction solution and mixed thoroughly (molar ratio of drug:mAb = 15:1). The reaction was incubated at 4°C and 600 rpm for 1 hour. A positive control, Farletuzumab-DXD, and a negative control, hIgG1-DXD, were prepared using the same method. After the reaction, the reaction solution was added to a 30Ka ultrafiltration tube. The solution volume was replaced by 6-8 times with a 10mM histidine hydrochloride solution, pH 6.0. After concentration to an appropriate volume, the solution was added to a equilibrated desalting column and centrifuged to obtain the purified ADC product. The final concentration of the ADC was determined using a Nanodrop microspectrophotometer, the purity of the ADC was determined by SEC-HPLC, and the DAR value of the ADC was determined by RP-HPLC / HIC-HPLC. The results are shown in Table 16. The structure of the anti-human FOLR1 antibody-DXD conjugate is shown in Figure 6.

[0293] Table 16. Characterization and analysis results of ADC prepared by coupling anti-human FOLR1 humanized antibody with DXD

[0294] Theoretically, a DAR value of about 8 can be obtained by fully reducing the interchain disulfide bonds of the antibody. DAR8 is the maximum drug loading capacity of traditional cysteine ​​interchain conjugation. The ADC prepared in this application has a higher DAR, indicating that a site-specific conjugated ADC has been obtained in this application.

[0295] 7.2 ADCs prepared by coupling humanized anti-human FOLR1 antibodies with DXD inhibit the growth of KB (human oral epidermoid carcinoma) cells

[0296] The KB (human oral epidermoid carcinoma) animal model was established using human immunodeficient mice (SCID Beige, CB17.Cg-PrkdcscidLystbg-J / Crl, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., strain code: 405) and the anti-tumor efficacy of different ADC molecules prepared by coupling anti-human FOLR1 antibodies with DXD was tested in this mouse tumor model. KB cells were diluted with serum-free medium (RPMI 1640), and then the corresponding volume of Matrigel (Cat. No.: 354234, BD) was added and mixed with the cell solution (RPMI 1640 medium: Matrigel = 7:3). After that, 5×10 6 The cells were inoculated subcutaneously in the right flank of SCID Beige mice. 3 At the time of administration, 5 mice were divided into groups and injected (iv) with the vehicle (His-HCl buffer), hIgG1-DXD 5 mg / kg (Isotype), Farletuzumab-DXD 5 mg / kg (positive control), hz115E3C9-H5L3-DXD 5 mg / kg, hz186D9A7-H1L1-DXD 5 mg / kg and hz182C2D11-H2L1-DXD 5 mg / kg at a volume of 10 mL / kg, respectively. The test samples were administered once. After administration, the tumor-bearing mice were housed normally, and the survival status of the tumor-bearing mice was observed. The body weight and tumor volume of the tumor-bearing mice were recorded every Tuesday and Friday for about 7 weeks. Mouse tumor volume measurement: The length and width of the mouse tumor were measured using a digital vernier caliper (500-151-30, Mitutoyo). The tumor was calculated according to the formula: TV = 1 / 2*L*W 2 mm 3 (TV: tumor volume; L: tumor length, W: tumor width).

[0297] As shown in Figure 7, during the experimental observation period, the overall weight of the tumor-bearing mice increased, indicating that the tumor-bearing mice had good tolerance to the anti-human FOLR1 antibody-DXD conjugate at this dose. The test substances hz115E3C9-H5L3-DXD, hz186D9A7-H1L1-DXD, and hz182C2D11-H2L1-DXD all showed significant anti-tumor effects at a dose of 5 mg / kg administered once via the tail vein. However, as the tumor continued to grow (as of day 64 after dosing), the hz186D9A7-H1L1-DXD molecule showed greater efficacy (tumor regression rate of 100%), followed by the hz115E3C9-H5L3-DXD molecule (tumor regression rate of 80%), and then the hz182C2D11-H2L1-DXD molecule (tumor regression rate of 60%).

[0298] 7.3 ADCs prepared by coupling humanized anti-human FOLR1 antibodies with DXD inhibit the growth of NCI-H441 (human lung adenocarcinoma) cells

[0299] The NCI-H441 human lung adenocarcinoma model was established using human immunodeficient mice (SCID Beige, CB17.Cg-PrkdcscidLystbg-J / Crl, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., strain code: 405) and the anti-tumor efficacy of different ADC molecules prepared by coupling the anti-human FOLR1 antibody DXD was tested in this mouse model. NCI-H441 cells were diluted with serum-free medium (RPMI 1640), and then the corresponding volume of Matrigel was added and mixed with the cell solution (RPMI 1640 medium:Matrigel = 7:3). After that, 5×10 6 The cells were inoculated subcutaneously in the right flank of SCID Beige mice. 3 At the same time, 5 mice were randomly divided into groups and injected into the tail vein with the following test samples at a dosage volume of 10 mL / kg: vehicle (His-HCL buffer), IgG1-Dxd 5 mg / kg (Isotype), Farletuzumab-DXD 5 mg / kg (positive control), hz115E3C9-H5L3-DXD 1 mg / kg, hz115E3C9-H5L3-DXD 5 mg / kg, hz186D9A7-H1L1-DXD 1 mg / kg, hz186D9A7-H1L1-DXD 5 mg / kg, hz182C2D11-H2L1-DXD 1 mg / kg and hz182C2D11-H2L1-DXD 5 mg / kg, respectively, for one dose. After administration, the tumor-bearing mice were raised normally and their survival was observed. The weight and tumor volume of the tumor-bearing mice were recorded every Tuesday and Friday. Mouse tumor volume measurement: The length and width of the mouse tumor were measured with a digital vernier caliper, and the tumor was calculated according to the formula: TV = 1 / 2*L*W 2 mm 3 (TV: tumor volume; L: tumor length, W: tumor width).

[0300] As shown in Figure 8, during the observation period, the tumor-bearing mice experienced overall weight gain, demonstrating good tolerance to the anti-human FOLR1 antibody-DXD conjugate at this dose. The test substances hz115E3C9-H5L3-DXD, hz186D9A7-H1L1-DXD, and hz182C2D11-H2L1-DXD demonstrated significant anti-tumor effects at both 1 mg / kg and 5 mg / kg doses following a single tail vein administration. The 5 mg / kg dose group performed significantly better than the 1 mg / kg group, demonstrating a clear dose-dependent effect.

[0301] sequence

Claims

1. An anti-FOLR1 antibody or antigen-binding fragment thereof that specifically binds FOLR1, comprising:1) three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised in the heavy chain variable region as set forth in SEQ ID NO: 4 and / or three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised in the light chain variable region as set forth in SEQ ID NO: 8;2) three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised in the heavy chain variable region as set forth in SEQ ID NO: 12 and / or three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised in the light chain variable region as set forth in SEQ ID NO: 16;3) three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised in the heavy chain variable region as set forth in SEQ ID NO: 20 and / or three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised in the light chain variable region as set forth in SEQ ID NO: 24; or4) three heavy chain CDRs (HCDR1, HCDR2, HCDR3) comprised in the heavy chain variable region as set forth in SEQ ID NO: 28 and / or three light chain CDRs (LCDR1, LCDR2, LCDR3) comprised in the light chain variable region as set forth in SEQ ID NO: 32.

2. An anti-FOLR1 antibody or antigen-binding fragment thereof that specifically binds FOLR1, comprising:1) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 1, 2 and 3; and / or LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 5, 6 and 7;2) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 9, 10 and 11; and / or LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 13, 14 and 15;3) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 17, 18 and 19; and / or LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 21, 22 and 23; or4) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 25, 26 and 27; and / or LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 29, 30 and 31.

3. The anti-FOLR1 antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising a heavy chain variable region and / or a light chain variable region, wherein:1) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 4, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 4, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 4, or consists of SEQ ID NO: 4, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 8, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 8, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 8, or consists of SEQ ID NO: 8;2) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 12, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 12, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 12, or consists of SEQ ID NO: 12, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 16, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 16, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 16, or consists of SEQ ID NO: 16;3) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 20, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 20, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 20, or consists of SEQ ID NO: 20, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 24, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 24, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 24, or consists of SEQ ID NO: 24; or4) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 28, or an amino acid sequence comprising one or more amino acidsubstitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 28, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 28, or consists of SEQ ID NO: 28, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 32, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 32, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 32, or consists of SEQ ID NO: 32;5) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 35, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 35, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 35, or consists of SEQ ID NO: 35, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 39, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 39, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 39, or consists of SEQ ID NO: 39;6) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 35, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 35, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 35, or consists of SEQ ID NO: 35, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 40, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 40, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 40, or consists of SEQ ID NO: 40;7) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 35, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 35, or an amino acid sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 35, or consists of SEQ ID NO: 35, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 41, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 41, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 41, or consists of SEQ ID NO: 41;8) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 35, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 35, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 35, or consists of SEQ ID NO: 35, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 42, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 42, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 42, or consists of SEQ ID NO: 42;9) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 36, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 36, or consists of SEQ ID NO: 36, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 39, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 39, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 39, or consists of SEQ ID NO: 39;10) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 36, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 36, or consists of SEQ ID NO: 36, and the lightchain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 40, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 40, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 40, or consists of SEQ ID NO: 40;11) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 36, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 36, or consists of SEQ ID NO: 36, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 41, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 41, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 41, or consists of SEQ ID NO: 41;12) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 36, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 36, or consists of SEQ ID NO: 36, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 42, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 42, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 42, or consists of SEQ ID NO: 42;13) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 37, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 37, or consists of SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 39, or an amino acid sequence comprising one or more amino acid substitutions (e.g.,conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 39, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 39, or consists of SEQ ID NO: 39;14) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 37, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 37, or consists of SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 40, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 40, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 40, or consists of SEQ ID NO: 40;15) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 37, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 37, or consists of SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 41, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 41, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 41, or consists of SEQ ID NO: 41;16) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 37, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 37, or consists of SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 42, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 42, or an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 42, or consists of SEQ ID NO: 42;17) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 51, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 51, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 51, or consists of SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;18) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 51, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 51, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 51, or consists of SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;19) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 51, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 51, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 51, or consists of SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;20) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;21) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;22) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;23) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acidsubstitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;24) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;25) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 52, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 52, or consists of SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 60, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 60, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 60, or consists of SEQ ID NO: 60;26) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;27) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;28) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;29) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the lightchain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;30) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;31) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 53, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 53, or consists of SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 60, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 60, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 60, or consists of SEQ ID NO: 60;32) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 54, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 54, or consists of SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g.,conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;33) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 54, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 54, or consists of SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;34) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 54, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 54, or consists of SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;35) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 54, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 54, or consists of SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;36) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 54, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 54, or consists of SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;37) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 61, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 61, or consists of SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;38) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 61, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 61, or consists of SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;39) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 61, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 61, or consists of SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;40) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 61, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 61, or consists of SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;41) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 61, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 61, or consists of SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;42) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acidsubstitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;43) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;44) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;45) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;46) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;47) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 62, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 62, or consists of SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 60, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 60, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 60, or consists of SEQ ID NO: 60;48) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the lightchain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;49) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;50) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;51) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g.,conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;52) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;53) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 63, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 63, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 63, or consists of SEQ ID NO: 63, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 60, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 60, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 60, or consists of SEQ ID NO: 60;54) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 55, or consists of SEQ ID NO: 55;55) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 56, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 56, or consists of SEQ ID NO: 56;56) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 57, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 57, or consists of SEQ ID NO: 57;57) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 58, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 58, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 58, or consists of SEQ ID NO: 58;58) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 59, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 59, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 59, or consists of SEQ ID NO: 59;59) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 64, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 64, or consists of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 60, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 60, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 60, or consists of SEQ ID NO: 60;60) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 43, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 43, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 43, or consists of SEQ ID NO: 43, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 47, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 47, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 47, or consists of SEQ ID NO: 47;61) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 43, or an amino acid sequence comprising one or more amino acidsubstitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 43, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 43, or consists of SEQ ID NO: 43, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 48, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 48, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 48, or consists of SEQ ID NO: 48;62) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 43, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 43, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 43, or consists of SEQ ID NO: 43, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 49, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 49, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 49, or consists of SEQ ID NO: 49;63) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 43, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 43, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 43, or consists of SEQ ID NO: 43, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 50, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 50, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 50, or consists of SEQ ID NO: 50;64) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 44, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 44, or an amino acid sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 44, or consists of SEQ ID NO: 44, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 47, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 47, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 47, or consists of SEQ ID NO: 47;65) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 44, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 44, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 44, or consists of SEQ ID NO: 44, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 48, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 48, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 48, or consists of SEQ ID NO: 48;66) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 44, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 44, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 44, or consists of SEQ ID NO: 44, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 49, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 49, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 49, or consists of SEQ ID NO: 49;67) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 44, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 44, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 44, or consists of SEQ ID NO: 44, and the lightchain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 50, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 50, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 50, or consists of SEQ ID NO: 50;68) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 45, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 45, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 45, or consists of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 47, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 47, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 47, or consists of SEQ ID NO: 47;69) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 45, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 45, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 45, or consists of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 48, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 48, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 48, or consists of SEQ ID NO: 48;70) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 45, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 45, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 45, or consists of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 49, or an amino acid sequence comprising one or more amino acid substitutions (e.g.,conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 49, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 49, or consists of SEQ ID NO: 49;71) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 45, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 45, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 45, or consists of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 50, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 50, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 50, or consists of SEQ ID NO: 50;72) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 46, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 46, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 46, or consists of SEQ ID NO: 46, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 47, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 47, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 47, or consists of SEQ ID NO: 47;73) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 46, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 46, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 46, or consists of SEQ ID NO: 46, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 48, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 48, or an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 48, or consists of SEQ ID NO: 48;74) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 46, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 46, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 46, or consists of SEQ ID NO: 46, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 49, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 49, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 49, or consists of SEQ ID NO: 49; or75) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 46, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 46, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 46, or consists of SEQ ID NO: 46, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 50, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 50, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 50, or consists of SEQ ID NO: 50.

4. The anti- FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising a constant region sequence, wherein at least a portion of the constant region sequence is a human consensus constant region sequence, preferably, the heavy chain constant region sequence is as set forth in SEQ ID NO: 33, and the light chain constant region sequence is as set forth in SEQ ID NO: 34.

5. The anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1-4, comprising a heavy chain and / or a light chain, wherein:1) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 65, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof,relative to SEQ ID NO: 65, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 65, or consists of SEQ ID NO: 65, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 66, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 66, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 66, or consists of SEQ ID NO: 66;2) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 67, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 67, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 67, or consists of SEQ ID NO: 67, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 68, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 68, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 68, or consists of SEQ ID NO: 68;3) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 69, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 69, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 69, or consists of SEQ ID NO: 69, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 70, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 70, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 70, or consists of SEQ ID NO: 70;4) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 71, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 71, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequenceof SEQ ID NO: 71, or consists of SEQ ID NO: 71, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 72, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 72, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 72, or consists of SEQ ID NO: 72;5) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 73, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 73, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 73, or consists of SEQ ID NO: 73, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 74, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 74, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 74, or consists of SEQ ID NO: 74;6) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 75, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 75, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 75, or consists of SEQ ID NO: 75, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 76, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 76, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 76, or consists of SEQ ID NO: 76;7) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 77, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 77, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 77, or consists of SEQ ID NO: 77, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 78, or an amino acid sequencecomprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 78, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 78, or consists of SEQ ID NO: 78;8) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 79, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 79, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 79, or consists of SEQ ID NO: 79, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 80, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 80, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 80, or consists of SEQ ID NO: 80;9) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 81, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 81, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 81, or consists of SEQ ID NO: 81, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 82, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 82, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 82, or consists of SEQ ID NO: 82;10) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 83, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 83, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 83, or consists of SEQ ID NO: 83, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 84, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 84, or anamino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 84, or consists of SEQ ID NO: 84;11) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 85, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 85, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 85, or consists of SEQ ID NO: 85, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 86, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 86, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 86, or consists of SEQ ID NO: 86;12) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 87, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 87, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 87, or consists of SEQ ID NO: 87, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 88, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 88, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 88, or consists of SEQ ID NO: 88;13) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 89, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 89, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 89, or consists of SEQ ID NO: 89, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 90, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 90, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98% or 99% identity to the amino acid sequence of SEQ ID NO: 90, or consists of SEQ ID NO: 90; or14) the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 91, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 91, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 91, or consists of SEQ ID NO: 91, and the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 92, or an amino acid sequence comprising one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions, or any combination thereof, relative to SEQ ID NO: 92, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 92, or consists of SEQ ID NO: 92.

6. The anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, wherein the antibody is a chimeric monoclonal antibody or a humanized monoclonal antibody.

7. The anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein the antigen-binding fragment is selected from Fab, Fab'-SH, Fv (e.g., scFv) or (Fab')2 fragments.

8. An antibody-drug conjugate having the structure Ab-(L-D)n, wherein Ab is the anti-FOLR1 antibody or antigen-binding fragment thereof that specifically binds FOLR1 according to any one of claims 1-7, L is a linker, D is a therapeutically active substance or pharmaceutically active ingredient, and n = 1-8.

9. The antibody-drug conjugate according to claim 8, wherein the therapeutically active substance or pharmaceutically active ingredient is a cytotoxin, a plant toxin, a small molecule toxin, a radioisotope, a maytansinoid, or a camptothecin derivative, such as MMAE or DXD.

10. The antibody-drug conjugate according to claim 8 or 9, wherein the linker is a protease-cleavable peptide linker, for example glycine-glycine-phenylalanine-glycine (GGFG) or MC-VC-PAB, preferably, the linker may further comprise, for example, a maleimide conjugated to a cysteine residue of the antibody.

11. The antibody-drug conjugate according to any one of claims 8-10, wherein the antibodydrug conjugate has the following structure:or12. The antibody-drug conjugate according to any one of claims 8-11, wherein the antibodydrug conjugate has an average DAR of 1 to 8, for example an average DAR of 3.0-5.0.

13. The antibody-drug conjugate according to any one of claims 8-12, wherein the Ab comprises:(1) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 1, 2 and 3 and LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 5, 6 and 7, or(2) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 9, 10 and 11 and LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 13, 14 and 15, or(3) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 17, 18 and 19 and LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 21, 22 and 23, or(4) HCDR1, HCDR2, HCDR3 comprising the sequences as set forth in SEQ ID NOs: 25, 26 and 27 and LCDR1, LCDR2, LCDR3 comprising the sequences as set forth in SEQ ID NOs: 29, 30 and 31.

14. The antibody-drug conjugate according to any one of claims 8-13, wherein the Ab comprises a heavy chain variable region and a light chain variable region, wherein:(1) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 40, or(2) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 36, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 41, or(3) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 40, or(4) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 41, or(5) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or(6) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or(7) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or(8) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or(9) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 54, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or(10) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or(11) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 56, or(12) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55, or(13) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 57, or(14) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 55.

15. The antibody-drug conjugate according to any one of claims 8-14, wherein the Ab comprises:1) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 65 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 66; or2) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 67 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 68; or3) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 69 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 70; or4) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 71 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 72; or5) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 73 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 74; or6) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 75 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 76; or7) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 77 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 78; or8) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 79 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 80; or9) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 81 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 82; or10) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 83 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 84; or11) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 85 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 86; or12) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 87 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 88; or13) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 89 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 90; or14) a heavy chain whose amino acid sequence is as set forth in SEQ ID NO: 91 and a light chain whose amino acid sequence is as set forth in SEQ ID NO: 92.

16. A nucleic acid molecule encoding the anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1-7.

17. A vector comprising the nucleic acid molecule according to claim 16.

18. A host cell comprising the vector according to claim 17 or the nucleic acid molecule according to claim 16.

19. A pharmaceutical composition comprising:1) the anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1-7, or the antibody-drug conjugate according to any one of claims 8-15, the nucleic acid molecule according to claim 16, the vector according to claim 17, or the host cell according to claim 18; and2) a pharmaceutically acceptable carrier.

20. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the anti-FOLR1 antibody or antigenbinding fragment thereof according to any one of claims 1-7, or the antibody-drug conjugate according to any one of claims 8-15, the nucleic acid molecule according to claim 16, the vector according to claim 17, the host cell according to claim 18, or the pharmaceutical composition according to claim 19.

21. Use of the anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1-7, or the antibody-drug conjugate according to any one of claims 8-15, the nucleic acid molecule according to claim 16, the vector according to claim 17, the host cell according to claim 18, or the pharmaceutical composition according to claim 19 in the manufacture of a medicament for treating cancer.

22. Use of the anti-FOLR1 antibody or antigen-binding fragment thereof according to any one of claims 1-7 in the manufacture of an antibody-drug conjugate for treating cancer.

23. The method according to claim 20, or the use according to claim 21 or 22, wherein the cancer is a cancer highly expressing FOLR1, such as ovarian cancer, triple-negative breast cancer, endometrial cancer, peritoneal cancer, and lung cancer.

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