Binding molecules binding PD-L1 and LAG-3
Inventors
Campbell, Jamie • Sandy, Nikole • Tuna, Mihriban • Wollerton Van Horck, Francisca • Everett, Katy Louise • Gaspar, Miguel • Kraman, Matthew • Kmiecik, Katarzyna • Faroudi, Mustapha • Fosh, Natalie • Hebeis, Barbara
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11214620-B2
Publication Date
2022-01-04
Expiration Date
Abstract
The present invention relates to antibody molecules which bind to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3). The antibody molecules preferably comprise a CDR-based antigen binding site for PD-L1, and a LAG-3 antigen binding site which may be located in two or more structural loops of a CH3 domain of the antibody molecule. The antibody molecules of the invention find application, for example, in cancer therapy.
Core Innovation
The invention relates to an antibody molecule that binds to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3). The antibody molecule comprises a CDR-based antigen binding site for PD-L1 and a LAG-3 antigen binding site located in a CH3 domain.
The LAG-3 antigen binding site comprises the amino acid sequences WDEPWGED (SEQ ID NO: 1) and PYDRWVWPDE (SEQ ID NO: 3). WDEPWGED is located in a first structural loop of the CH3 domain, and PYDRWVWPDE is located in a second structural loop of the CH3 domain.
The document further characterizes the bispecific format as providing simultaneous LAG-3/PD-L1 binding and engagement across targets. It also describes reduced immune effector functions associated with an Fc modification (LALA mutation in CH2) while retaining tumor-cell killing features, and reports that T cell activation occurs only when both targets are inhibited.
The document states synergy in murine tumor models with improved tumor growth suppression versus separate LAG-3 and PD-L1 antibody combinations.
Claims Coverage
The independent claims are directed to a bispecific antibody molecule with two inventive elements: a PD-L1 CDR-based antigen binding site and a CH3-domain LAG-3 antigen binding site with specific amino-acid motifs positioned in structural loops.
PD-L1 CDR-based antigen binding site and CH3-domain LAG-3 binding site
An antibody molecule which binds to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3), wherein the antibody molecule comprises a CDR-based antigen binding site for PD-L1 and a LAG-3 antigen binding site located in a CH3 domain.
LAG-3 binding motifs positioned in structural loops of the CH3 domain
A LAG-3 antigen binding site comprising the amino acid sequences WDEPWGED (SEQ ID NO: 1) and PYDRWVWPDE (SEQ ID NO: 3), wherein WDEPWGED is located in a first structural loop of the CH3 domain and PYDRWVWPDE is located in a second structural loop of the CH3 domain.
Overall, the claim coverage centers on a bispecific antibody that combines a PD-L1 CDR-based binding site with a CH3-domain LAG-3 binding site defined by specific amino-acid motifs and their positioning in structural loops.
Stated Advantages
Enhanced IFN-γ activation in an antigen-presenting cell/T-cell co-culture assay for LAG-3/PD-L1 mAb2 combinations versus single-agent controls.
Improved tumor growth suppression and/or reduced tumor establishment in murine tumor models compared with benchmark separate anti-LAG-3 and anti-PD-L1 antibodies.
Dual blockade reduces LAG-3 expression on tumor-infiltrating lymphocytes, as evidenced by flow cytometry.
Introducing the LAG-3 binding site into the PD-L1 antibody preserves PD-L1-targeted effector activity, while an Fc LALA mutation is described as abrogating ADCC and affecting CDC parameters.
Reduced immune effector functions via LALA mutation in CH2 while retaining tumor-cell killing features.
T cell activation only when both targets are inhibited.
Synergy in murine tumor models with improved tumor growth suppression versus separate LAG-3 and PD-L1 antibody combinations.
Documented Applications
Functional evaluation of a bispecific anti-LAG-3/PD-L1 antibody (mAb2) in vitro using SEB-driven and cytokine ELISA assays with an antigen-presenting cell/T-cell co-culture readout of IFN-γ activation.
In vivo evaluation in multiple murine tumor models, including MC38 and CT26 (non-established and established), for tumor growth suppression and/or reduction of tumor establishment using the LAG-3/PD-L1 mAb2 relative to benchmark separate anti-LAG-3 and anti-PD-L1 antibodies.
Mechanism assessment of dual blockade effect on LAG-3 expression on tumor-infiltrating lymphocytes using flow cytometry.
Fc effector function characterization involving ADCC and CDC measurements using target cell populations expressing PD-L1 or LAG-3 and evaluating effects associated with Fc modifications, including LALA.
Treating cancer in a patient by administering a therapeutically effective amount of the antibody molecule.
Interested in licensing this patent?