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Published July 2010 | Accepted Version
Journal Article Open

A dimeric form of the HIV-1 antibody 2G12 elicits potent antibody-dependent cellular cytotoxicity


Objective: Increasing data support a role for antibody-dependent cellular cytotoxicity (ADCC) in controlling HIV-1 infection. We recently isolated a naturally occurring dimeric form of the anti-HIV-1 antibody 2G12 and found it to be significantly more potent than 2G12 monomer in neutralizing primary virus strains. However, given the unusual structure of dimeric 2G12 with two Fc regions, it was not clear whether 2G12 dimer could bind to the CD16 Fc receptor on ADCC effector cells or trigger ADCC. Here we compared the in-vitro ADCC activities of 2G12 monomer and dimer and investigated the effects of including ADCC-enhancing mutations in both forms of 2G12. Methods: An in-vitro ADCC assay using target cells stably expressing gp160 was developed to evaluate the activities of 2G12 monomer and dimer with and without ADCC-enhancing mutations that increase the CD16-binding affinity of the 2G12 Fc region. Results: Both 2G12 monomer and 2G12 dimer elicited ADCC, although the dimer showed increased potency [lower half-maximal concentration (EC50)] in triggering ADCC, thus confirming its ability to bind CD16 and trigger ADCC. The ADCC-enhancing mutations improved the ADCC activity of 2G12 monomer more than 2G12 dimer such that their EC50 values were nearly equal. However, no increase in nonspecific ADCC activity was observed using 2G12 IgGs with these mutations. Conclusion: Given the likelihood that ADCC plays a role in protecting against initial infection and/or controlling chronic infection, these data suggest 2G12 dimers and/or addition of ADCC-enhancing mutations could augment the prophylactic and/or therapeutic potential of 2G12.

Additional Information

© 2010 Wolters Kluwer Health; Lippincott Williams & Wilkins. Received: 1 February 2010; revised: 31 March 2010; accepted: 10 April 2010. We thank Drs Jost Vielmetter and Tal Arnon for advice about the ADCC assay, Christopher Foglesong and the Caltech Protein Expression Center for expressing 2G12, Dr Sanjeev Nandakumaran (Kaiser Permanente Southern California Medical Group) for purified rituximab, and Kathryn Huey-Tubman, Matt Thornton, AnthonyWest, and Fan Yang for critical reading of the manuscript. This work was supported by the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative, the Collaboration for AIDS Vaccine Discovery, the Howard Hughes Medical Institute, and an NIH National Research Service Award 5 T32 GM07616 (A.W).

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