Multi-chain polypeptide-containing tri-specific binding molecules

Inventors

Johnson, Leslie S. • Huang, Ling • Chichili, Gurunadh Reddy • Shah, Kalpana • Lam, Chia-Ying Kao • Burke, Stephen James • Liu, Liqin • Moore, Paul A. • Bonvini, Ezio • Barat, Bhaswati

Assignees

Macrogenics Inc

Abstract

The present invention relates to Tri-Specific Binding Molecules, which are multi-chain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes. The Binding Domains may be selected such that the Tri-Specific Binding Molecules are capable of binding to any three different epitopes. Such epitopes may be epitopes of the same antigen or epitopes of two or three different antigens. In a preferred embodiment, one of such epitopes will be capable of binding to CD3, the second of such epitopes will be capable of binding to CD8, and the third of such epitopes will be capable of binding to an epitope of a Disease-Associated Antigen. The invention also provides a novel ROR1-binding antibody, as well as derivatives thereof and uses for such compositions.

Core Innovation

The invention provides a multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes. The molecule comprises three different polypeptide chains covalently complexed together and includes an Antigen-Binding Domain I, an Antigen-Binding Domain II, and an Antigen-Binding Domain III that respectively bind Epitope I, Epitope II, and Epitope III. Antigen-Binding Domains I and II are Diabody-Type Binding Domains, and Antigen-Binding Domain III is a Non-Diabody-Type Binding Domain.

The Fc Domain is formed by association of CH2-CH3 domains of the first and third polypeptide chains. The first polypeptide chain includes VL1 Domain, VHII Domain, a Heterodimer-Promoting Domain, and a CH2-CH3 Domain, and the second polypeptide chain includes VLII Domain, VHI Domain, and a Heterodimer-Promoting Domain. The third polypeptide chain includes VHIII Domain and a cysteine-containing domain together with a CH2-CH3 Domain.

The document further defines specific chain architectures and domain orderings, including arrangements of VL and VH domains linked by Linker 1, Linker 2, Linker 3, and Linker 4 together with a heterodimer-promoting domain and a CH2-CH3 Domain. Linker compositions, cysteine-containing domains, and CH2-CH3 Domain configurations are specified, and the Heterodimer-Promoting Domain is defined as an E-coil Domain and a K-coil Domain, in either E-coil/K-coil or K-coil/E-coil placement.

The document also specifies that VL1 and VH1 form Antigen-Binding Domain I, VL2 and VH2 form Antigen-Binding Domain II, and VL3 and VH3 form Antigen-Binding Domain III. Covalent coupling is described using cysteine-containing domains and cysteine-based elements, and the CH2-CH3 Domains are defined as knob-bearing or hole-bearing and configured reciprocally across the polypeptide chains.

Claims Coverage

The independent claim identified is clm-00001. It defines one tri-specific multi-chain polypeptide architecture with three antigen-binding domains and an Fc Domain, centered on binding three epitopes, forming two diabody-type domains and one non-diabody-type domain, and assembling the Fc Domain by CH2-CH3 association. The claim set also includes defined chain architectures, linker selections, and heterodimer-promoting domains.

The claim coverage centers on a covalently complexed three-chain tri-specific binding molecule with three epitope-binding domains, two diabody-type binding domains, one non-diabody-type binding domain, and an Fc Domain formed from CH2-CH3 association. It further constrains the architecture with specified linker sequence selections, E-coil/K-coil heterodimer-promoting domains, and defined light/heavy variable domain roles for Epitope I, Epitope II, and Epitope III binding.

Stated Advantages

Documented Applications