Single-Arm Monovalent Antibody Constructs and Uses Thereof

摘要

Provided herein are monovalent antibody constructs. In specific embodiments is a monovalent antibody construct comprising: an antigen-binding polypeptide construct which monovalently binds an antigen; and a dimeric Fc polypeptide construct comprising a CH3 domain, said construct comprising two monomeric Fc polypeptides, wherein one said monomeric Fc polypeptide is fused to at least one polypeptide from the antigen-binding polypeptide construct. These therapeutically novel molecules encompass monovalent constructs that display an increase in binding density and Bmax (maximum binding at a target to antibody ratio of 1:1) to a target cell displaying said antigen as compared to a corresponding monospecific bivalent antibody construct with two antigen binding regions. Provided herein are methods for creation of monovalent antibody constructs that shows superior effector efficacy as compared to the corresponding bivalent antibody construct at equimolar concentrations. Provided herein are methods for creation of monovalent antibody constructs that unexpectedly inhibit tumor cell growth and can be internalized and show greater efficacy compared to a bivalent antibody construct at equimolar saturating concentrations. Provided are monovalent antibody constructs for the treatment of HER2 expressing diseases.

主权项

1. An isolated monovalent antibody construct comprising:
an antigen-binding polypeptide construct which monovalently binds an antigen; and a dimeric Fc polypeptide construct, said Fc polypeptide construct comprising two monomeric Fc polypeptides each comprising a CH3 domain, wherein one said monomeric Fc polypeptide is fused to at least one polypeptide from the antigen-binding polypeptide construct; wherein said monovalent antibody construct selectively and/or specifically binds a target cell displaying said antigen with:
an increased binding density and Bmax as compared to a corresponding monospecific bivalent antibody construct with two antigen binding regions;a dissociation constant (Kd) comparable to said monospecific bivalent antibody construct;an off-rate that is comparable or slower that said monospecific bivalent antibody construct; and wherein said monovalent antibody construct displays biophysical and in vivo stability comparable to said monospecific bivalent antibody construct; and on-target cytotoxicity comparable to or greater than said monospecific bivalent antibody construct.