Antibody homotypic interactions are encoded by germline light chain complementarity determining region 2

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 transien...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 23; p. 1
Main Authors Leonard, Brandon, Sankar, Kannan, Romei, Matthew G, Tse, Margaret J, Do, Nina, Yang, Yanli, Matochko, Wadim L, Bevers, Jack, Bollineni, Sundeep, Mukhyala, Kiran, Hoi, Kam Hon, Lazar, Greg A
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 07.06.2022
Subjects
Antibodies
Antigens
Avidity
Biology
Chains
Complementarity
Fab
Interfaces
Monoclonal antibodies
Receptor mechanisms
Self-association
Somatic hypermutation
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.220156211