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CN-122029201-A - Methods of treating hematological disorders with monospecific antibodies targeting VWF

CN122029201ACN 122029201 ACN122029201 ACN 122029201ACN-122029201-A

Abstract

Provided herein are antibodies, compositions, and methods of use thereof. The disclosed antibodies bind von Willebrand factor in the plasma of the subject. Such antibodies may be used in therapeutic methods, such as methods of treating one or more blood conditions characterized by excessive bleeding.

Inventors

  • H. Ostergard
  • P. S. Gandhi
  • J. H. Faber
  • C. Liya
  • B. Solenson
  • MIKE HAIGH

Assignees

  • 赫马布公司

Dates

Publication Date
20260512
Application Date
20240816
Priority Date
20230816

Claims (20)

  1. 1. A monospecific antibody comprising an antigen binding site that specifically binds to an epitope of Von Willebrand Factor (VWF) protein located in the Cysteine Knot (CK) domain, and a crystallizable fragment (Fc) region, wherein binding of the antibody to the VWF protein in plasma results in accumulation of the VWF protein in plasma compared to the plasma level of the VWF protein in the absence of the antibody.
  2. 2. The monospecific antibody of claim 1, wherein the antibody comprises a heavy chain Variable (VH) region having an amino acid sequence at least 80% identical to SEQ ID No. 488 and a light chain Variable (VL) region having an amino acid sequence at least 80% identical to SEQ ID No. 522.
  3. 3. The monospecific antibody of claim 1, wherein the antibody comprises a VH comprising therein a Complementarity Determining Region (CDR) H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 523, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 524 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 518.
  4. 4. The monospecific antibody of claim 1 wherein the antibody comprises a first HC comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 689 or 731, and an LC comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 690.
  5. 5. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 45, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 577 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 578.
  6. 6. The monospecific antibody of claim 1, wherein the antibody comprises a first HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 699, and an LC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 700.
  7. 7. The monospecific antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID No. 488 and a VL having an amino acid sequence at least 80% identical to SEQ ID No. 505.
  8. 8. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 506, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 507 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 493.
  9. 9. The monospecific antibody of claim 1, wherein the antibody comprises a first HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 685, and an LC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 686.
  10. 10. The monospecific antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID No. 488 and a VL having an amino acid sequence at least 80% identical to SEQ ID No. 575.
  11. 11. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of 544, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 524 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of 527.
  12. 12. The monospecific antibody of claim 1, wherein the antibody comprises a first HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 697, and an LC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 698.
  13. 13. The monospecific antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID No. 488 and a VL having an amino acid sequence at least 80% identical to SEQ ID No. 490.
  14. 14. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of 491, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 492 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 493.
  15. 15. The monospecific antibody of claim 1, wherein the antibody comprises a first HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 683, and an LC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 684.
  16. 16. The monospecific antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID No. 488 and a VL having an amino acid sequence at least 80% identical to SEQ ID No. 519.
  17. 17. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 520, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 521 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 493.
  18. 18. The monospecific antibody of claim 1, wherein the antibody comprises a first HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 473, a second HC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 687, and an LC comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 688.
  19. 19. The monospecific antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID No. 528 and a VL having an amino acid sequence at least 80% identical to SEQ ID No. 530.
  20. 20. The monospecific antibody of claim 1 wherein the antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 529, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 513, a CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 531 and a CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 46.

Description

Methods of treating hematological disorders with monospecific antibodies targeting VWF Cross Reference to Related Applications The present application claims the benefit and priority of U.S. provisional patent application No. 63/519,955 filed on 8/16 of 2023, the entire contents of which are hereby incorporated by reference for all purposes. Sequence listing The present specification refers to a sequence table that has been electronically submitted in XML format and is hereby incorporated by reference in its entirety. The XML file was created at 2024, 8/5, under the name HMT-005WO_SL.xml, and has a size of 678 kb. Disclosure of Invention In certain embodiments, disclosed herein are compositions and methods for treating a blood disorder using a monospecific antibody directed against Von Willebrand Factor (VWF). In certain embodiments, disclosed herein are monospecific antibodies comprising an antigen binding site that specifically binds to an epitope of Von Willebrand Factor (VWF) protein located in the Cysteine Knot (CK) domain, and a crystallizable fragment (Fc) region, wherein binding of an antibody disclosed herein to VWF protein results in accumulation of VWF protein in plasma compared to the plasma level of VWF protein in the absence of the antibody. In some embodiments, the antibody comprises a heavy chain Variable (VH) region having an amino acid sequence with at least 80% identity to SEQ ID NO. 488 and a light chain Variable (VL) region having an amino acid sequence with at least 80% identity to SEQ ID NO. 522. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 85% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 85% identity to SEQ ID NO. 522. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 90% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 90% identity to SEQ ID NO. 522. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 95% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 95% identity to SEQ ID NO. 522. In some embodiments, the antibody comprises a VH having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 488 and a VL having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 522. in some embodiments, an antibody comprises a VH comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, and a VL comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 523, CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 524 and CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID No. 518. In some embodiments, an antibody comprises (a) a VH having an amino acid sequence with at least 80% identity to SEQ ID NO. 488 and comprising therein a CDR H1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 41, a CDR H2 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 42 and a CDR H3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 489, a VL having an amino acid sequence with at least 80% identity to SEQ ID NO. 522 and comprising therein a CDR L1 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID NO. 523, CDR L2 having an amino acid sequence 100% identical to the amino acid sequence of 524 and CDR L3 having an amino acid sequence 100% identical to the amino acid sequence of SEQ ID No. 518. in some embodiments, the antibody comprises a first Heavy Chain (HC) region comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 473, a second HC region comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 689 or 731, and a Light Chain (LC) region comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 690. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 80% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 80% identity to SEQ ID NO. 576. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 85% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 85% identity to SEQ ID NO. 576. In some embodiments, the antibody comprises a VH having an amino acid sequence with at least 90% identity to SEQ ID NO. 488 and a VL having an amino acid sequence with at least 90% identity to SEQ ID NO. 576. In some embodiments, the antibody comprises