Multispecific Antibody Development Platform Based on Human Heavy Chain Antibodies

Area of Science:

• Immunology
• Biotechnology
• Molecular Biology

Background:

• Heavy chain-only antibodies (HCAbs) offer advantages as antibody-based biologics due to their small, functional V_H domains.
• Natural human V_H regions require light chain association and exhibit poor stability when expressed alone, hindering HCAb development.

Purpose of the Study:

• To develop a platform for generating diverse, stable, high-affinity human heavy chain-only antibodies (HCAbs) selected in vivo.
• To overcome the limitations of producing functional human HCAbs without light chain association.

Main Methods:

• Utilized transgenic rats (UniRats) engineered with large human heavy chain V(D)J repertoires.
• Immunized UniRats with antigens to elicit immune responses and select for HCAbs.
• Combined antibody repertoire analysis with immunization for rapid HCAb development.

Main Results:

• UniRats successfully produced chimeric HCAbs with fully human V_H domains.
• Demonstrated robust immune responses and diverse V gene usage in UniRats.
• Generated large panels of stable, high-affinity, antigen-specific human HCAbs.

Conclusions:

• The UniRat platform enables rapid, in vivo selection of diverse human HCAbs.
• This approach overcomes challenges in producing functional human HCAbs, facilitating antibody-based biologic development.