ArticleProceedings of the National Academy of Sciences of the United States of America2022
Antibody homotypic interactions are encoded by germline light chain complementarity determining region 2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 7 citations in OpenAlex.
- Realizing the potential of agonistic antibody immunotherapy.Nature reviews. Drug discovery · 2026Review
- Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy.Nature communications · 2025Article
- A Phase I Clinical Trial Adding OX40 Agonism to In Situ Therapeutic Cancer Vaccination in Patients with Low-Grade B-cell Lymphoma Highlights Challenges in Translation from Mouse to Human Studies.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists.Nature communications · 2024Article
- Joined at the hip: The role of light chain complementarity determining region 2 in antibody self-association.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Antibody interfaces revealed through structural mining.Computational and structural biotechnology journal · 2022Article
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12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The utilization of avidity to drive and tune functional responses is fundamental to antibody biology and often underlies the mechanisms of action of monoclonal antibody drugs. There is increasing evidence that antibodies leverage homotypic interactions to enhance avidity, often through weak transient interfaces whereby self-association is coupled with target binding. Here, we comprehensively map the Fab–Fab interfaces of antibodies targeting DR5 and 4-1BB that utilize homotypic interaction to promote receptor activation and demonstrate that both antibodies have similar self-association determinants primarily encoded within a germline light chain complementarity determining region 2 (CDRL2). We further show that these determinants can be grafted onto antibodies of distinct target specificity to substantially enhance their activity. An expanded characterization of all unique germline CDRL2 sequences reveals additional self-association sequence determinants encoded in the human germline repertoire. Our results suggest that this phenomenon is unique to CDRL2, and is correlated with the less frequent antigen interaction and lower somatic hypermutation associated with this loop. This work reveals a previously unknown avidity mechanism in antibody native biology that can be exploited for the engineering of biotherapeutics.
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Registered trials
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