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JP-2026076267-A - Anti-tissue factor antibodies, antibody-drug conjugates, and related methods

JP2026076267AJP 2026076267 AJP2026076267 AJP 2026076267AJP-2026076267-A

Abstract

[Problem] To provide an antibody that specifically binds to human tissue factor (TF), an anti-TF antibody drug conjugate (ADC), and a composition containing the antibody or ADC. [Solution] An isolated human antibody is provided that binds to the extracellular domain of human tissue factor (TF), wherein the isolated human antibody binds to human TF at a human TF binding site separate from the human TF binding site to which human FVIIa binds. [Selection Diagram] None

Inventors

  • トイニッセン ヤン－ヴィレム
  • エイヴリー アンドリュー ディー． セカンド
  • カイ アレン ジー．
  • クーパー アンソニー バイロン
  • ミゴーネ シ－サウ

Assignees

  • アイコニック セラピューティクス リミテッド ライアビリティ カンパニー

Dates

Publication Date
20260511
Application Date
20260123
Priority Date
20180104

Claims (14)

  1. An antibody that binds to the extracellular domain of human tissue factor (TF), The aforementioned antibody VH-CDR1, VH-CDR2, and VH-CDR3 each contain the amino acid sequences of VH-CDR1, VH-CDR2, and VH-CDR3, respectively, which are represented by VH containing the amino acid sequence of SEQ ID NO: 151. The VL contains the amino acid sequences of VL-CDR1, VL-CDR2, and VL-CDR3, respectively, which are represented by the VL containing the amino acid sequence of SEQ ID NO: 152. The VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are determined by the Kabat numbering scheme, Chothia numbering scheme, AbM numbering scheme, Contact numbering scheme, or IMGT numbering scheme. The antibody.
  2. An antibody comprising VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 that binds to the extracellular domain of human TF, (i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 115, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 116, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 117, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 118, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 119, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 120. (ii) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 121, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 122, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 123, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 124, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 125, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 126. (iii) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 127, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 128, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 129, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 130, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 131, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 132. (iv) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 133, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 134, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 135, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 136, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 137, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 138. (v) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 139, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 140, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 141, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 142, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 143, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 144, or (vi) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 145, VH-CDR2 contains the amino acid sequence of SEQ ID NO: 146, VH-CDR3 contains the amino acid sequence of SEQ ID NO: 147, VL-CDR1 contains the amino acid sequence of SEQ ID NO: 148, VL-CDR2 contains the amino acid sequence of SEQ ID NO: 149, and VL-CDR3 contains the amino acid sequence of SEQ ID NO: 150. The antibody.
  3. The antibody according to claim 1, comprising the VH sequence of SEQ ID NO: 151 and the VL sequence of SEQ ID NO: 152.
  4. A monoclonal antibody, as described in any one of claims 1 to 3.
  5. An antibody according to any one of claims 1 to 4, comprising Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, a single-chain antibody molecule, a bivariable domain antibody, or a linear antibody.
  6. An antibody according to any one of claims 1 to 4, comprising an Fc region.
  7. An antibody according to any one of claims 1 to 4, comprising a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  8. An antibody according to any one of claims 1 to 4, comprising a heavy chain constant region of the IgG class and a subclass selected from IgG1, IgG2, IgG3, and IgG4.
  9. An isolated polynucleotide or set of polynucleotides encoding the antibody or its antigen-binding portion according to any one of claims 1 to 8.
  10. A vector or set of vectors comprising a polynucleotide or a set of polynucleotides as described in claim 9.
  11. A host cell comprising the polynucleotide or set of polynucleotides described in claim 9.
  12. A method for producing an antibody, comprising the steps of expressing the antibody using host cells as described in claim 11, and isolating the expressed antibody.
  13. A pharmaceutical composition comprising the antibody described in any one of claims 1 to 8 and a pharmaceutically acceptable excipient.
  14. (i) an antibody according to any one of claims 1 to 8, (ii) A kit including an instruction manual.

Description

Cross-reference of related applications This application claims the interests of U.S. Provisional Applications No. 62/613,545, No. 62/613,564, No. 62/646,788, No. 62/613,797, and No. 62/713,804, filed on 4 January 2018, each of which is incorporated herein by reference in whole. Sequence Listing This application includes a sequence listing submitted via EFS-Web, which is incorporated herein by reference in its entirety. A copy of the ASCII file prepared on XX/XX/20XX is named XXXXXUS_sequencelisting.txt and is X,XXX,XXX bytes in size. Background Blood coagulation involves a series of complex processes that result in clotting. Tissue factor (TF) plays a crucial role in these coagulation processes. TF is the cell surface receptor for serine protease factor VIIa (FVIIa). The TF/FVIIa complex catalyzes the conversion of inactive protease factor X (FX) to active protease factor Xa (FXa). FXa and its cofactor FVa form the prothrombinase complex, which generates thrombin from prothrombin. Thrombin converts soluble fibrinogen into insoluble fibrin chains and catalyzes many other coagulation-related processes. TF is overexpressed on several types of solid tumors. In cancer, TF/FVIIa signaling may support angiogenesis, tumor progression, and metastasis. Increased TF expression can also induce inflammation and/or angiogenesis in many other diseases, including exudative age-related macular degeneration (AMD) and diabetic retinopathy. Summary This specification provides antibodies that specifically bind to human tissue factor (TF), anti-TF antibody drug conjugates, and related methods. In one embodiment, this specification provides an isolated human antibody that binds to the extracellular domain of human tissue factor (TF) at a human TF binding site separate from the human TF binding site to which human FVIIa binds. In some embodiments, (1) the isolated antibody does not inhibit human thrombinogenesis when determined by a thrombinogenesis assay (TGA) compared to a reference antibody containing the VH sequence of SEQ ID NO: 821 and the VL sequence of SEQ ID NO: 822, and (2) when determined by the median fluorescence intensity of the isolated antibody compared to an isotype control in a live cell staining assay, the binding between the isolated antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the isolated antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, (1) the isolated antibody inhibits human thrombinogenesis to a lower degree compared to a reference antibody containing the VH sequence of SEQ ID NO: 821 and the VL sequence of SEQ ID NO: 822, as determined by a thrombinogenesis assay (TGA), and (2) the binding between the isolated antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the isolated antibody compared to an isotype control in a live cell staining assay, is less than 50% of the binding between the isolated antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, (1) the isolated antibody tolerates human thrombin generation to a greater extent than a reference antibody containing the VH sequence of SEQ ID NO: 821 and the VL sequence of SEQ ID NO: 822, as determined by a thrombin generation assay (TGA), and (2) the binding between the isolated antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the isolated antibody compared to an isotype control in a live cell staining assay, is less than 50% of the binding between the isolated antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, (1) the isolated antibody inhibits human thrombinogenesis by a smaller amount compared to a reference antibody containing the VH sequence of SEQ ID NO: 821 and the VL sequence of SEQ ID NO: 822, as determined by a thrombinogenesis assay (TGA), and (2) the binding between the isolated antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the isolated antibody compared to an isotype control in a live cell staining assay, is less than 50% of the binding between the isolated antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, (1) the isolated antibody, as determined by a thrombin generation assay (TGA), tolerates a greater amount of human thrombin generation compared to a reference antibody containing the VH sequence of SEQ ID NO: 821 and the VL sequence of SEQ