Killer cell lectin-like receptor subfamily G member 1 (KLRG1) depleting antibodies
Inventors
Gulla, Stefano Vincenzo • Thompson, Kenneth Evan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11180561-B2
Publication Date
2021-11-23
Expiration Date
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
The disclosure describes KLRG1 depleting antibodies that specifically bind to the extracellular domain of KLRG1. The antibodies comprise defined heavy chain variable regions and light chain variable regions with complementarity determining regions (CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3) specified by multiple SEQ ID NO sets.
The disclosed antibodies bind an epitope PLNFSRI (SEQ ID NO:56) that is described as distinct from the cadherin ligand interface, and they are characterized as non-competing with cadherin ligands including E-cadherin, N-cadherin, and R-cadherin. Functional characterization distinguishes non-blocking versus blocking activity using an IFN-γ readout, while preserving KLRG1 co-inhibitory checkpoint function.
The disclosure further describes selective depletion of pathogenic T/NK cells while maintaining apparent sparing of naïve/Treg subsets in non-human primates, including cynomolgus monkeys. Antibody generation and selection is summarized at an overview level, together with binding and functional characterization such as in vitro binding kinetics (Octet KD) and EC50 measurements.
Claims Coverage
The independent claims are directed to KLRG1-binding antibody or fragment constructs defined by extracellular-domain specificity and multiple alternative CDR/variable-region sequence sets, with inventive features centered on defined heavy- and light-chain CDR complements and specified epitope-related binding while allowing sequence identity variants. Across the independent claims, the inventive coverage is defined by a small set of core sequence/region constraints and extends to formulations and kit formats via dependent claims.
Extracellular-domain binding antibody with defined CDR sets
An antibody, or fragment thereof, that specifically binds to an extracellular domain of KLRG1 and comprises a heavy chain variable region with three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and a light chain variable region with three light chain complementary determining regions (CDR-L1, CDR-L2 and CDR-L3), wherein the antibody comprises SEQ ID NOs for CDR-H1/CDR-H2/CDR-H3 and CDR-L1/CDR-L2/CDR-L3 selected from the listed SEQ ID NO sets.
Extracellular-domain binding antibody with specified CDR-H and CDR-L sequences
An antibody, or fragment thereof, that specifically binds to an extracellular domain of KLRG1 and comprises a heavy chain with three heavy chain complementarity determining regions comprising SEQ ID NO:28 (CDR-H1), SEQ ID NO:29 (CDR-H2), and SEQ ID NO:30 (CDR-H3) and a light chain with three light chain complementarity determining regions comprising SEQ ID NO:31 (CDR-L1), SEQ ID NO:32 (CDR-L2), and SEQ ID NO:33 (CDR-L3).
Extracellular-domain binding antibody with specified variable-region reference sequences
An antibody, or fragment thereof, that specifically binds to an extracellular domain of KLRG1 and comprises a heavy chain comprising SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30; a light chain comprising SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33; wherein the heavy chain variable region comprises SEQ ID NO:8 or a sequence at least 90% identical to SEQ ID NO:8; and wherein the light chain variable region comprises SEQ ID NO:9 or a sequence at least 90% identical to SEQ ID NO:9.
Extracellular-domain binding antibody with specified alternative variable-region reference sequences
An antibody, or fragment thereof, that specifically binds to an extracellular domain of KLRG1 and comprises a heavy chain comprising SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30; a light chain comprising SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33; wherein the heavy chain variable region comprises SEQ ID NO:54 or a sequence at least 90% identical to SEQ ID NO:54; and wherein the light chain variable region comprises SEQ ID NO:55 or a sequence at least 90% identical to SEQ ID NO:55.
Overall, the claim coverage centers on antibodies or fragments that specifically bind the extracellular domain of KLRG1 and are defined by heavy-chain and light-chain complementarity determining regions and associated variable-region SEQ ID reference sequences, with sequence identity thresholds to define covered sequence variants. Additional coverage is provided in dependent claims for pharmaceutical compositions including a pharmaceutically acceptable carrier and kit formats including packaging materials.
Stated Advantages
Preserves KLRG1 co-inhibitory checkpoint function while depleting pathogenic T/NK cells.
Provides selective depletion with apparent sparing of naïve/Treg subsets in non-human primates.
Binds a KLRG1 epitope that is distinct from the cadherin ligand interface.
Does not compete with cadherin ligands (E-cadherin, N-cadherin, R-cadherin).
Documented Applications
Use in depleting pathogenic T/NK cells while preserving KLRG1 co-inhibitory checkpoint function.
Use in selective depletion in non-human primates, with apparent sparing of naïve/Treg subsets.
Use in pharmaceutical compositions and kit formats including a pharmaceutically acceptable carrier and packaging materials.
Interested in licensing this patent?