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EP-3268392-B1 - ACTIVATABLE ANTI-PDL1 ANTIBODIES, AND METHODS OF USE THEREOF

EP3268392B1EP 3268392 B1EP3268392 B1EP 3268392B1EP-3268392-B1

Inventors

  • WEST, James William
  • MEI, LI
  • MOORE, STEPHEN JAMES
  • NGUYEN, Margaret
  • HOSTETTER, Daniel
  • Vasiljeva, Olga
  • SAGERT, JASON
  • TERRETT, JONATHAN

Dates

Publication Date
20260506
Application Date
20160314

Claims (16)

  1. An activatable antibody that, in an activated state, specifically binds to mammalian PDL1, wherein said activatable antibody comprises: an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PDL1, wherein the AB comprises: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 212; (b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246; (c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 235; (d) a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209; (e) a variable light chain complementarity determining region 2 (VL CDR2) comprising the amino acid sequence of SEQ ID NO: 215; and (f) a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228; a masking moiety (MM) that inhibits the binding of the AB to mammalian PDL1 when the activatable antibody is in an uncleaved state, wherein the MM consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 63 and 71; and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease, wherein the CM consists of the amino acid sequence of SEQ ID NO: 377; wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length, and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM.
  2. The activatable antibody of claim 1, wherein the activatable antibody comprises a variable light chain comprising the amino acid sequence of SEQ ID NO: 58 and a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 46.
  3. The activatable antibody of claim 1 or 2, wherein the antigen binding fragment thereof is selected from the group consisting of a Fab fragment, a F(ab')2 fragment, a scFv, and a scAb.
  4. The activatable antibody of any one of claims 1 to 3, wherein the two linking peptides are not identical to each other.
  5. The activatable antibody of claim 2, wherein the activatable antibody comprises the amino acid sequence of SEQ ID NO: 985.
  6. The activatable antibody of claim 2, wherein the activatable antibody comprises the amino acid sequence of SEQ ID NO: 137.
  7. The activatable antibody of claim 1, wherein the activatable antibody comprises the amino acid sequence of SEQ ID NO: 428 or SEQ ID NO: 1008.
  8. The activatable antibody of any of claims 1 to 7, wherein the activatable antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 430, SEQ ID NO: 432, SEQ ID NO: 434, and SEQ ID NO: 1202.
  9. An activatable antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432.
  10. A conjugated activatable antibody comprising the activatable antibody of any one of claims 1 to 9 conjugated to an agent, optionally wherein the agent is conjugated to the activatable antibody via a linker.
  11. A pharmaceutical composition comprising the activatable antibody of any one of claims 1 to 9, or the conjugated activatable antibody of claim 10, and a carrier.
  12. The pharmaceutical composition of claim 11, further comprising an additional agent.
  13. An isolated nucleic acid molecule encoding the activatable antibody of any one of claims 1 to 9.
  14. A vector comprising the isolated nucleic acid molecule of claim 13.
  15. A method of producing an activatable antibody by culturing a cell under conditions that lead to expression of the activatable antibody, wherein the cell comprises the nucleic acid molecule of claim 13, and optionally conjugating an agent to the activatable antibody.
  16. The activatable antibody of any one of claims 1 to 9, the conjugated activatable antibody of claim 10, or the pharmaceutical composition of any of claims 11 or 12, for use in the treatment of a cancer.

Description

Field of the Invention The invention relates generally to antibodies that bind programmed death ligand 1 (PDL1), activatable antibodies that specifically bind to PDL1 and methods of making and using these anti-PDL1 antibodies and anti-PDL1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications. Background of the Invention Antibody-based therapies have proven effective treatments for several diseases but in some cases, toxicities due to broad target expression have limited their therapeutic effectiveness. In addition, antibody-based therapeutics have exhibited other limitations such as rapid clearance from the circulation following administration. In the realm of small molecule therapeutics, strategies have been developed to provide prodrugs of an active chemical entity. Such prodrugs are administered in a relatively inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into the active compound. Such prodrug strategies can provide for increased selectivity of the drug for its intended target and for a reduction of adverse effects. Accordingly, there is a continued need in the field of antibody-based therapeutics for antibodies that mimic the desirable characteristics of the small molecule prodrug. WO 2011/066389 A1 relates to human monoclonal antibodies directed against B7-H1 and uses of these antibodies in diagnostics and for the treatment of diseases associated with the activity and/or expression of B7-H1. Additionally, hybridomas or other cell lines expressing such antibodies are disclosed. WO 2015/013671 A1 relates generally to multispecific antibodies and to multispecific activatable antibodies that specifically bind two or more different antigens or epitopes, as well as to methods of making and using these multispecific antibodies and/or multispecific activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications. WO 2013/163631 A2 relates generally to activatable antibodies that include a masking moiety (MM), a cleavable moiety (CM), and an antibody (AB) that specifically binds to epidermal growth factor receptor (EGFR), and to methods of making and using these anti- EGFR activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications. Summary of the Invention The invention provides an activatable antibody that, in an activated state, specifically binds to mammalian PDL1, wherein said activatable antibody comprises: an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PDL1, wherein the AB comprises: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 212;(b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246;(c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 235;(d) a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209;(e) a variable light chain complementarity determining region 2 (VL CDR2) comprising the amino acid sequence of SEQ ID NO: 215; and(f) a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228;a masking moiety (MM) that inhibits the binding of the AB to mammalian PDL1 when the activatable antibody is in an uncleaved state, wherein the MM consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 63 and 71; anda cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease, wherein the CM consists of the amino acid sequence of SEQ ID NO: 377;wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length, and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. The invention provides an isolated nucleic acid molecule encoding the activatable antibody as described herein. The invention provides a method of producing an activatable antibody by culturing a cell under conditions that lead to expression of the activatable antibody, wherein the cell comprises the nucleic acid molecule described herein, and optionally conjugating an agent to the activatable antibody. The invention provides an activatable antibody, conjugated activatable antibody or the pharmaceutical composition as described herein, for use in the treatment of a cancer. The disclosure provides antibodies or antigen-binding fragments thereof that specifically bind programmed death ligand 1 (PDL1), also known as PD-L1, CD274, B7 homolog 1 and/or B7-H1. The use of the term "PDL1" is intended to co