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

Common light chain chickens produce human antibodies of high affinity and broad epitope coverage for the engineering of bispecifics

Kathryn H Ching  1 , Kimberley Berg  1   2 , Kevin Reynolds  1 , Darlene Pedersen  1 , Alba Macias  3 , Yasmina N Abdiche  4 , William D Harriman  1 , Philip A Leighton  1
Affiliations

Common light chain chickens produce human antibodies of high affinity and broad epitope coverage for the engineering of bispecifics

Kathryn H Ching et al. MAbs. 2021 Jan-Dec.

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. Abbreviations: AID: activation-induced cytidine deaminase; bsAb: bispecific antibody; CDR: complementarity-determining region; CL: light chain constant region; CmLC: common light chain; D: diversity region; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; Fc: fragment crystallizable; FcRn: neonatal Fc receptor; FR: framework region; GEM: gel-encapsulated microenvironment; Ig: immunoglobulin; IMGT: the international ImMunoGeneTics information system®; J: joining region; KO: knockout; mAb: monoclonal antibody; NGS: next-generation sequencing; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PGC: primordial germ cell; PGRN: progranulin; TCR: T cell receptor; V: variable region; VK: kappa light chain variable region; VL: light chain variable region; VH: heavy chain variable region.

Keywords: Bispecific; antibody engineering; common light chain; human antibodies; transgenic chicken.

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Figures

Figure 1.
Figure 1.
CmLC1 transgene structure
Figure 2.
Figure 2.
Analysis of bulk NGS sequencing data from OmniClic compared to OmniChicken
Figure 3.
Figure 3.
Frequency of mutations in anti-PGRN mAbs cloned with native light chains
Figure 4.
Figure 4.
Sequence dendrogram, epitope binning and mouse cross-reactivity of all anti-PGRN clones (native and germline light chain)
Figure 5.
Figure 5.
Binding kinetics
Figure 6.
Figure 6.
Pairing the same VH with its native VK or germline VK
See this image and copyright information in PMC

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