Selective depletion of ABO-responsive B cells by T-cell–engaging bispecific antibody conjugates for ABOi transplantation
Abstract
Abstract Organ transplantation is a pivotal treatment for patients with organ failure. ABO-incompatible (ABOi) transplantation, developed to expand the donor pool, presents significant clinical challenges due to preexisting antibodies targeting ABO antigens on donor organs. Current therapies using broad B-cell depletion, such as rituximab, effectively reduce antibody-mediated rejection but increase infection risks. Therefore, there is a critical need for targeted methods to specifically eliminate ABO-responsive B cells. Here, we developed a novel bispecific antibody-ligand conjugate (BiALC) platform designed to selectively target ABO-responsive B cells. Using synthetic trisaccharide A antigens conjugated to T-cell–recruiting Fab fragments, our optimized hexameric construct, (A3-peg)2-αCD3, demonstrated enhanced affinity and potent cytotoxicity specifically against type A antigen–responsive B cells. Notably, BiALC maintained robust efficacy even in the presence of circulating anti-A antibodies. In murine models, (A3-peg)2-αCD3 selectively depleted A-responsive B cells without broadly affecting total immunoglobulin M–positive (IgM+) and IgG+ B-cell populations, preserving overall immune competence. Similarly, the human-compatible BiALC, (A3-peg)2-αhCD3, effectively and selectively depleted type A–responsive B cells from human peripheral blood mononuclear cells, with potency comparable with that of rituximab, while sparing total antibody-secreting cells. Overall, the BiALC strategy offers a promising antigen-specific approach to reduce rejection risks in ABOi transplantation without inducing broad immunosuppression through nonspecific pan–B-cell depletion, supporting its potential for clinical translation.
Article Details
Authors (15)
Hyeong Ryeol Choi
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Honglin Piao
3Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea
Shafrizal Rasyid Atriardi
6Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, Republic of Korea
In Kang
7Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Taekyung Chang
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Serin Kim
8College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Joon Young Jang
4Division of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
Gwang-Min Lee
3Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea
Kyeong Cheon Jung
9Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Hanifah Mardhiyah
6Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, Republic of Korea
Fazsa Islamianti Machmud
6Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, Republic of Korea
Jin Park
Sang Kook Woo
6Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, Republic of Korea
Jaeseok Yang
Chan Hyuk Kim
2Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea