Bispecific CD16-binding molecules and their use in the treatment of disease

Inventors

Diedrich, Gundo • Liu, Liqin • LI, HUA WATSON • Johnson, Leslie S.

Assignees

Macrogenics Inc

Abstract

The present invention is directed to molecules (e.g., an antibody, a diabody, an scFv, an antibody, a TandAb, etc.) capable of binding an epitope of human CD16 (a “CD16 Binding Molecule”). The present invention is further directed to CD 16 Binding Molecules that are capable of binding an epitope of human CD16 and one or more epitope(s) of a Disease Antigen (“DA”) (e.g., a “CD16×DA Binding Molecule”). The present invention is particularly directed to such CD16×DA Binding Molecules that are antibodies, or that comprise an Epitope Binding Domain thereof, or are diabodies (including DART® diabodies), bispecific antibodies, TandAbs, other multispecific binding molecules (e.g., trivalent TRIDENT™ molecules), etc. The invention particularly concerns CD16×DA Binding Molecules that are capable of binding a Disease Antigen that is a Cancer Antigen or a Pathogen-Associated Antigen in addition to being able to bind CD 16. The invention particularly concerns the use of such CD16 and CD16×DA Binding Molecules in the treatment of cancer and pathogen-associated diseases. The present invention is also directed to pharmaceutical compositions that comprise such molecule(s).

Core Innovation

The invention relates to CD16×Disease Antigen (CD16×DA) binding molecules that redirect immune effector cells toward cells expressing a disease antigen. The CD16 binding domain binds an epitope of CD16 and enables ADCC via FcγR interactions, and the approach improves co-localization of CD16-expressing cells to disease antigen sites through the dual binding arrangement.

The CD16×DA binding molecules are configured with a CD16 Binding Domain and a Disease Antigen-Binding Domain, where each domain includes antibody variable heavy (VH) and variable light (VL) domains comprising CDR1, CDR2, and CDR3 regions. Structural embodiments include diabodies, including DART® diabodies, TandAbs, TRIDENT™ trivalent molecules, and bispecific constructs including CARs, with embodiments with and without an Fc region, including Fc-containing diabodies and Fc engineering options.

The document further specifies Fc and variant Fc modifications, including IgG1, IgG2, IgG3, and IgG4 isotypes, and amino acid substitutions to reduce FcγR affinity and/or enhance serum half-life using Kabat/EU index numbering. The disease antigen targets are described as cancer antigens and pathogen-associated antigens, with named examples for the Disease Antigen-Binding Domain such as margetuximab, trastuzumab, pertuzumab, bevacizumab, 5T4, CD123, CD19, 7B2, A32, vPalivizumab, Enoblituzumab, and hu08.

The invention also provides engineered Fc CH2/CH3 amino-acid sequences for IgG1 and IgG4 that incorporate L234A and L235A substitutions to reduce or abolish FcγR effector function, M252Y, S254T, and T256E substitutions to extend serum half-life, and an optional S442C substitution for covalent CH3-CH3 bonding or drug conjugation. Additional Fc heterodimerization mutations prevent CH2-CH3 homodimerization in Fc-containing diabodies and trivalent binding molecules, and the Protein A binding domain is retained only on the heterodimer partner.

Claims Coverage

The provided claim set contains three independent claims, directed to a CD16×Disease Antigen (CD16×DA) binding molecule and to CD16 binding molecules defined by specific CDR sequence sets. Across the independent claims, the inventive coverage centers on antibody variable-region compositions, and the patent text also describes Fc region variants and Fc heterodimerization features.

Across the independent claims, coverage is centered on antibody variable-region definition for CD16 binding using enumerated SEQ ID NO-based CDR compositions, and, for the CD16×DA molecule, on combining that CD16 Binding Domain with a Disease Antigen-Binding Domain formed from the VL/VH domains of specific named therapeutic antibodies mapped to specific SEQ ID NOs.

Stated Advantages

Documented Applications