Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof

Inventors

Liu, Liqin • Lam, Chia-Ying Kao • Diedrich, Gundo • Johnson, Leslie S. • Moore, Paul A. • Bonvini, Ezio

Assignees

Macrogenics Inc

Abstract

The present invention is directed to binding molecules that possess one or more epitope-binding sites specific for an epitope of CD137 and one or more epitope-binding sites specific for an epitope of a tumor antigen (“TA”) (e.g., a “CD137×TA Binding Molecule”). In one embodiment, such CD137×TA Binding Molecules will be bispecific molecules, especially bispecific tetravalent diabodies, that are composed of two, three, four or more than four polypeptide chains and possessing two epitope-binding sites each specific for an epitope of CD137 and two epitope-binding sites each specific for an epitope of a TA. Alternatively, such CD137×TA Binding Molecules will be bispecific molecules, especially bispecific trivalent binding molecules composed of three or more polypeptide chains and possessing one or two epitope-binding sites each specific for an epitope of CD137 and one or two epitope-binding sites each specific for an epitope of a TA. The CD137×TA Binding Molecules of the invention are capable of simultaneous binding to CD137, and a TA. The invention is directed to pharmaceutical compositions that contain any such CD137×TA Binding Molecules. The invention is additionally directed to methods for the use of such molecules in the treatment of cancer and other diseases and conditions. The invention also provides novel CD137-binding molecules, and HER2/neu-binding molecules, as well as derivatives thereof and uses thereof.

Core Innovation

The invention relates to CD137×tumor-antigen (TA) binding molecules capable of specific binding to an epitope of CD137 and an epitope of a tumor antigen. The molecules include a CD137 binding domain and a TA binding domain, with defined first and second light chain variable domains and heavy chain variable domains, each having CDRL1, CDRL2, CDRL3 and CDRH1, CDRH2, CDRH3.

The document describes CD137×TA binding molecules configured as bispecific tetravalent diabodies, bispecific trivalent binding formats, DART® diabody formats, five-chain Fc diabodies, and Fc-bearing variants and engineered multichain constructs. It further describes covalently assembled heterodimers/multichain constructs and heterodimer-promoting domain formats with Fc modifications.

The constructions include Fc heterodimerization using knob and hole substitutions in the CH2-CH3 regions together with a Protein A binding site mutation, and IgG1/IgG4 CH2-CH3 variants with reduced FcγR binding. The document also provides extensive SEQ ID mappings for parental and optimized domains and related structural features.

Claims Coverage

The consolidated claim coverage centers on a CD137×TA binding molecule with defined CD137-binding and TA-binding variable-domain CDR sets. Across the provided items, the inventive features comprise one core claim set with dependent refinements specifying alternative CD137-binding CDR selections, constrained tumor antigen selection, named TA-binding CDR sets for HER2/neu and 5T4, and a pharmaceutical composition with a physiologically acceptable carrier.

Overall, the claim coverage centers on a CD137×TA binding molecule defined by explicit CDR selections for both the CD137 binding domain and the TA binding domain, with dependent claims narrowing the CD137-binding CDR variants, constraining TA selection to a defined set, specifying HER2/neu and 5T4 TA-binding CDR sets, and adding a pharmaceutical composition including a physiologically acceptable carrier.

Stated Advantages

Documented Applications