Bispecific molecules comprising an HIV-1 envelope targeting arm

Inventors

Haynes, Barton F. • Ferrari, Guido • Koenig, Scott • Johnson, Leslie S. • Lam, Chia-Ying Kao • SUNG, Julia A. • Margolis, David M. • Liu, Liqin • Nordstrom, Jeffrey Lee

Assignees

University of North Carolina at Chapel Hill • Macrogenics Inc • Duke University

Abstract

The invention is directed to bispecific molecules comprising an HIV-1 envelope targeting arm and an arm targeting an effector cell, compositions comprising these bispecific molecule and methods of use. In certain aspects, the bispecific molecules of the present invention can bind to two different targets or epitopes on two different cells within the first epitope is expressed on a different cell type than the second epitope, such that the bispecific molecules can bring the two cells together. In certain aspects, the bispecific molecules of the present invention can bind to two different cells, wherein the bispecific molecules comprises an arm with the binding specificity of A32, 7B2, CH27, CH28 or CH44.

Core Innovation

The invention provides a bispecific molecule comprising a first polypeptide chain and a second polypeptide chain covalently bonded to one another. The first polypeptide chain includes a domain (A) with a binding region of a light chain variable domain from HIV-1 antibody A32 or 7B2, a domain (B) with a binding region of a heavy chain variable domain from an antibody specific for an epitope of CD3 or CD16, and a domain (C) comprising a heterodimer promoting domain including a K coil or E coil.

The second polypeptide chain includes a domain (D) with a binding region of a light chain variable domain of an antibody specific for the epitope of CD3 or CD16, a domain (E) with a binding region of a heavy chain variable domain of HIV-1 antibody A32 or 7B2, and a domain (F) comprising a heterodimer promoting domain including a K coil or E coil. The molecule is configured such that domains (A) and (B) do not associate and form an epitope binding site, and domains (D) and (E) do not associate to form an epitope binding site.

Instead, domains (A) and (E) associate to form a binding site that binds the HIV-1 envelope like the A32 or 7B2 antibody, and domains (B) and (D) associate to form a binding site that binds the epitope of CD3 or CD16. The K coil and E coil are defined by residues 240-267 of SEQ ID NO:19 and residues 249-276 of SEQ ID NO:17, and peptide linker 2 is defined by residues 244-248 of SEQ ID NO:17.

The disclosure includes Fc-bearing three-chain variants built from CH2-CH3 domains and optional Fc engineering, and composition formats that frame therapeutic use including targeting HIV-infected cells and latently infected cells after latency activation with a latency activating agent. Documented embodiments include constructs that simultaneously bind HIV-1 envelope and CD3 or CD16 to redirect effector cells for killing of HIV-infected cells, including autologous reservoir virus after latency activation.

Claims Coverage

Independent claim clm-00001 covers one bispecific molecule with two covalently bonded polypeptide chains and four inventive features: defined domain order and linkers, enforced non-association and cross-association rules, residue-defined K/E coil and peptide linker 2 segments, and CDR-defined binding regions for the HIV-1 antibody arm and the CD3 or CD16 arm.

The independent claim defines a bispecific molecule that selectively assembles two binding sites by using covalently linked polypeptide chains with defined variable-domain CDR contents, peptide linkers, and K coil/E coil heterodimer promoting domains. It explicitly prevents association of certain domain pairs and instead enforces association of (A) with (E) for HIV-1 envelope binding and (B) with (D) for CD3 or CD16 epitope binding, with residue-defined coil and peptide linker 2 segments.

Stated Advantages

Documented Applications