Common Light Chain Chickens Produce Human Antibodies of High Affinity and Broad Epitope Coverage for the Engineering of Bispecifics

MAbs. Jan-Dec 2021;13(1):1862451. doi: 10.1080/19420862.2020.1862451.

Kathryn H. Ching, Kimberley Berg, Kevin Reynolds, Darlene Pedersen, Alba Macias, Yasmina N. Abdiche, William D. Harriman, Philip A. Leighton

Abstract

Bispecific antibodies are an important and growing segment in antibody therapeutics, particularly in the immuno-oncology space. Manufacturing of a bispecific antibody with two different heavy chains is greatly simplified if the light chains can be the same for both arms of the antibody. Here, we introduce a strain of common light chain chickens, called OmniClic®, that produces antibody repertoires largely devoid of light chain diversity. The antibody repertoire in these chickens is composed of diverse human heavy chain variable regions capable of high-affinity antigen-specific binding and broad epitope diversity when paired with the germline human kappa light chain. OmniClic birds can be used in immunization campaigns for discovery of human heavy chains to different targets. Subsequent pairing of the heavy chain with a germline human kappa light chain serves to facilitate bispecific antibody production by increasing the efficiency of correct pairing.

Introduction

Bispecific antibodies (bsAbs) comprise a diverse collection of novel molecules in various formats and configurations designed to bind two distinct epitopes or targets at the same time. The pipeline of bsAbs in pharmaceutical development is quite large and diverse, with goals such as retargeting T effector cells to tumor cells, chaperoning proteins across the blood-brain barrier, anti-inflammatory effects, and increasing avidity by binding multiple epitopes on the same cell. In the case of retargeting of T cells to tumor cells, one arm of the bsAb is often specific for the CD3 delta or epsilon chains of the T cell receptor complex, and the other arm specific for a receptor on the tumor cells. To date, three bsAbs have been granted marketing approvals, although currently only two are on the market (blinatumomab (Blincyto®), for acute B-cell lymphoblastic leukemia, and emicizumab (Hemlibra®), for treating hemophilia A). With over 85 potential bsAbs in clinical development, this number is likely to rise.