Methods of treating disorders associated with excess or unwanted killer cell lectin-like receptor subfamily g member 1 (KLRG1) expressing t cells with KLRG1 depleting antibodies

Inventors

Gulla, Stefano Vincenzo • Thompson, Kenneth Evan

Assignees

Abcuro Inc

Abstract

The receptor killer cell lectin-like receptor G1 (KLRG1) is expressed on T and NK cells, which binds to ligands on epithelial and mesenchymal cells. The ligand for KLRG1 has been described to be E-cadherin, N-cadherin, and R-cadherin. The present disclosure relates to and results from the discovery and characterization of antibodies that bind the extracellular domain (ECD) of KLRG1 but do not interfere with its interaction with the ligands E-cadherin, N-cadherin, and R-cadherin. The antibodies described have been derived by mouse hybridoma technology, and can be humanized by grafting their complementary determining regions (CDRs) into a human framework. The antibodies described can be used as effective therapeutic agents. Various antibodies, or antigen-binding fragments of such antibodies, along with various therapeutic and/or diagnostic methods, among other features, are provided for in the present disclosure.

Core Innovation

Killer cell lectin-like receptor G1 (KLRG1) is described as a binding cadherin ligand that binds E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRG1. The disclosed antibodies specifically bind an extracellular domain of KLRG1 and do not interfere with binding by E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRG1.

The document discloses non-interfering anti-KLRG1 antibodies and antigen-binding fragments that bind the KLRG1 extracellular domain but do not compete with cadherin binding. Delivery is described as depleting excess or unwanted KLRG1-expressing T cells, and in some contexts KLRG1-expressing pathogenic T cells and/or NK cells attacking self-tissues or transplanted tissues.

The antibodies are defined by heavy chain and light chain variable regions comprising three heavy chain complementarity determining regions and three light chain complementarity determining regions. The document provides multiple enumerated combinations of SEQ ID NOs for the CDRs, and describes an epitope mapping to PLNFSRI distinct from the cadherin interface, with stated binding and functional distinctions including blocking versus non-blocking behavior.

Therapeutic use is described for disorders associated with excess or unwanted KLRG1 expressing T cells, including cancer and adjunct therapy in subjects undergoing checkpoint therapy, as well as autoimmune disease and transplant disorders. The document further describes pharmaceutical compositions and kits comprising the antibodies or fragments, and describes antibody humanization using mouse hybridomas and variable region specifications based on SEQ ID NOs and CDR sets.

Claims Coverage

The provided claims include four independent claims covering treatment of disorders associated with excess or unwanted KLRG1-expressing T cells, treatment of cancer comprising cancer cells that express KLRG1, adjunct therapy for cancer during checkpoint therapy, and depletion of KLRG1-expressing cells in a mixed population. Across these independent claims, the inventive features are centered on delivering a therapeutically effective amount of an anti-KLRG1 antibody that binds the KLRG1 extracellular domain without interfering with cadherin binding, with antibody variable regions defined by enumerated CDR sets using SEQ ID NOs.

Across the independent claims, the scope is directed to anti-KLRG1 antibodies that bind the KLRG1 extracellular domain without interfering with cadherin binding, and that achieve depletion of KLRG1-expressing cells in treatment settings for disorders associated with excess or unwanted KLRG1-expressing T cells, cancer, and adjunct checkpoint therapy. The antibody is further restricted by heavy- and light-chain variable regions containing enumerated CDR sets defined by SEQ ID NO combinations.

Stated Advantages

Documented Applications