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WO-2026092728-A1 - ANTI-IGF-1R ANTIBODY CONSTRUCTS AND USES THEREOF

WO2026092728A1WO 2026092728 A1WO2026092728 A1WO 2026092728A1WO-2026092728-A1

Abstract

An anti-IGF-1R antibody or antigen-binding fragment thereof is provided. Further provided are pharmaceutical compositions thereof, methods of producing the anti-IGF-1R antibody or antigen-binding fragment thereof, methods of using the anti-IGF-1R antibody or antigen-binding fragment thereof for treatment of diseases such as thyroid eye disease of fibrosis, and kits comprising the anti-IGF-1R antibody or antigen-binding fragment thereof.

Inventors

  • LI, YIMING
  • LI, LI
  • GAO, JIANHUA
  • CAO, Yuling

Assignees

  • INNOVENT BIOLOGICS (SUZHOU) CO., LTD.
  • FORTVITA BIOLOGICS INC.

Dates

Publication Date
20260507
Application Date
20251103
Priority Date
20241104

Claims (20)

  1. An anti-IGF-1R antibody or antigen-binding fragment thereof, comprising: a) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 8, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 9. b) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 13, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 15; c) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 10, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 11; d) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 12, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 15; e) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 14, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 15; f) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 1, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 2; g) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 3, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 4; h) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 3, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 5; or i) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V H chain region having the sequence set forth in SEQ ID NO: 6, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a V L chain region having the sequence set forth in SEQ ID NO: 7.
  2. The anti-IGF-1R antibody or antigen-binding fragment thereof of claim 1, wherein: a) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 or 39, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31, 37, or 40, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, 36, or 38, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or 41, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; or b) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or 48, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, 28, or 29, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27.
  3. The anti-IGF-1R antibody or antigen-binding fragment thereof of claim 1 or 2, wherein: a) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 39 or 50, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 40, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 41, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; b) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or 48, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 28, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; c) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or 48, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; d) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or 48, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; e) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 or 49, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:33, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; f) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 or 49, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; or g) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 or 49, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35.
  4. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-3, wherein: a) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 45 or 51, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 43, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; or b) the V H comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or 48, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24; and the V L comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27.
  5. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-4, comprising a variable region of heavy chain, wherein the variable region of heavy chain comprises: i) an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity to any one of SEQ ID NOs: 1, 3, 6, 8, 10, 12, 13, and 14; or ii) an amino acid sequence of any one of SEQ ID NOs: 1, 3, 6, 8, 10, 12, 13, and 14.
  6. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-5, comprising a variable region of light chain, wherein the variable region of light chain comprises: i) an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity to any one of SEQ ID NOs: 2, 4, 5, 7, 9, 11, and 15; or ii) an amino acid sequence of any one of SEQ ID NOs: 2, 4, 5, 7, 9, 11, and 15.
  7. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein: a) the V H comprises an amino acid sequence of SEQ ID NO: 8, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; b) the V H comprises an amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; c) the V H comprises an amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; d) the V H comprises an amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; e) the V H comprises an amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; f) the V H comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; g) the V H comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; h) the V H comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; or i) the V H comprises an amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity; and the V L comprises an amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99%sequence identity.
  8. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-7, wherein: a) the V H comprises an amino acid sequence of SEQ ID NO: 8, and the V L comprises an amino acid sequence of SEQ ID NO: 9; b) the V H comprises an amino acid sequence of SEQ ID NO: 12, and the V L comprises an amino acid sequence of SEQ ID NO: 15; c) the V H comprises an amino acid sequence of SEQ ID NO: 13, and the V L comprises an amino acid sequence of SEQ ID NO: 15; d) the V H comprises an amino acid sequence of SEQ ID NO: 13, and the V L comprises an amino acid sequence of SEQ ID NO: 15; e) the V H comprises an amino acid sequence of SEQ ID NO: 10, and the V L comprises an amino acid sequence of SEQ ID NO: 11; f) the V H comprises an amino acid sequence of SEQ ID NO: 1, and the V L comprises an amino acid sequence of SEQ ID NO: 2; g) the V H comprises an amino acid sequence of SEQ ID NO: 3, and the V L comprises an amino acid sequence of SEQ ID NO: 4 or 5; or h) the V H comprises an amino acid sequence of SEQ ID NO: 6, and the V L comprises an amino acid sequence of SEQ ID NO: 7.
  9. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-8, wherein the anti-IGF-1R antibody or antigen-binding fragment thereof is selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab’ fragment, a F (ab’ ) 2 , an Fv fragment, a disulfide stabilized Fv fragment (dsFv) , a (dsFv) 2 , a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, and a tetrabody.
  10. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the anti-IGF-1R antibody or antigen-binding fragment thereof is a full-length antibody.
  11. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-10, comprising an Fc fragment is selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof.
  12. The anti-IGF-1R antibody or antigen-binding fragment thereof of claim 11, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.
  13. The anti-IGF-1R antibody or antigen-binding fragment thereof of claim 11 or 12, wherein the Fc fragment comprises an amino acid sequence of SEQ ID NO: 47 or 52.
  14. The anti-IGF-1R antibody or antigen-binding fragment thereof of claim 11 or 12, wherein the Fc fragment comprises one or more mutations selected from the group consisting of: L234A/L235A, S364R, D399K, Y349T, K370S, and K409D compared to a reference Fc set forth in SEQ ID NO: 47 or 52.
  15. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-14, wherein the anti-IGF-1R antibody or antigen-binding fragment thereof is a chimeric anti-IGF-1R antibody or antigen-binding fragment thereof.
  16. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-15, wherein the anti-IGF-1R antibody or antigen-binding fragment thereof is a humanized anti-IGF-1R antibody or antigen-binding fragment thereof.
  17. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-16, wherein the anti-IGF-1R antibody or antigen-binding fragment thereof is monoclonal.
  18. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-17, wherein the V H comprises an amino acid sequence of SEQ ID NO: 8, and the V L comprises an amino acid sequence of SEQ ID NO: 9.
  19. The anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-17, wherein the V H comprises an amino acid sequence of SEQ ID NO: 13, and the V L comprises an amino acid sequence of SEQ ID NO: 15.
  20. A pharmaceutical composition comprising the anti-IGF-1R antibody or antigen-binding fragment thereof of any one of claims 1-19, and a pharmaceutical acceptable carrier.

Description

ANTI-IGF-1R ANTIBODY CONSTRUCTS AND USES THEREOF TECHNICAL FIELD The present disclosure relates to anti-IGF-1R antibody constructs (such as anti-IGF-1R antibodies and antigen-binding fragments thereof) and the uses thereof. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (701672001340SEQLIST. xml; Size: 54,878 bytes; and Date of Creation: October 31, 2024) is herein incorporated by reference in its entirety. BACKGROUND OF THE APPLICATION Insulin-like growth factor 1 receptor (IGF-1R) is a trans-membrane tyrosine kinase expressed in almost every mammalian cell. Studies in tissue-specific experimental models revealed a central role for IGF-1R signaling in regulating glucose metabolic functions in the liver, skeletal muscles, and adipose tissue. In addition to healthy tissues, IGF-1R is commonly over-expressed, and the signaling pathway constitutively activated in numerous cancers contributing to mesenchymal transition of stroma cells and malignant development. IGF-1R acts at the crossroad between cancer and immunity. IGF-1R is broadly expressed in macrophages and, under physiological conditions, sufficient IGF-1R signaling keeps the balance between pro-and anti-inflammatory activities of these cells. Studies have demonstrated that conditional deletion of IGF-1R in myeloid progenitors results in the upregulation of the key anti-inflammatory markers in macrophages. Upon pathogen challenge, IGF-1R-deficient macrophages exhibited reduced accumulation in lesions and poor phagocytic ability. IGF-1R signaling in leukocytes is associated with activation of STAT3 and STAT5 proteins, which initiates dominant expression of RORγt and NF-κB transcription factors and acquisition of the effector phenotype of Th17 cells. Such a shift in the regulatory balance of T cells following IGF-1R inhibition has been recognized in several autoimmune conditions including multiple sclerosis, rheumatoid arthritis, and type I diabetes mellitus. Together, this points out the important role of IGF-1R plays in the pathogenesis of aberrant T cell self-recognition. A different mode of IGF-1R dependent autoimmunity has been described in thyroiditis, where IGF-1R bearing B cells are responsible for the production of pathogenic antibodies against the thyrotropin receptor. See, e.g., Erlandsson et al. (2022) Front. Immunol. 13: 958206. While various later-stage clinical trials of anti-IGF-1R blocking antibodies to treat cancer failed to show significant clinical benefit, their therapeutic potential in preventing or treating autoimmune disease (s) remains to be elucidated. The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety. BRIEF SUMMARY OF THE APPLICATION The present application in one aspect provides an anti-IGF-1R antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL) , wherein the anti-IGF-1R antibody or antigen-binding fragment thereof comprises: a) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 8, and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 9; b) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 13, and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 15; c) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 10, and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 11; d) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 12, and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 15; e) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 14, and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 15; f) an HC-CDR1, an HC-CDR2, and an HC-CDR3, resp