CATG & Merck find an aB that binds to the same target as Fuzeon:
>>Published online before print October 3, 2005
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0506927102
Medical Sciences
A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope
( envelope | fusion | prehairpin | vaccine )
Michael D. Miller *, Romas Geleziunas *, Elisabetta Bianchi ¶, Simon Lennard ||, Renee Hrin *, Hangchun Zhang *, Meiqing Lu *, Zhiqiang An **, Paolo Ingallinella ¶, Marco Finotto ¶, Marco Mattu ¶, Adam C. Finnefrock **, David Bramhill **, James Cook **, Debra M. Eckert **, Richard Hampton **, Mayuri Patel **, Stephen Jarantow **, Joseph Joyce **, Gennaro Ciliberto ¶, Riccardo Cortese ¶, Ping Lu **, William Strohl **, William Schleif **, Michael McElhaugh **, Steven Lane ||, Christopher Lloyd ||, David Lowe ||, Jane Osbourn ||, Tristan Vaughan ||, Emilio Emini **, Gaetano Barbato ¶, Peter S. Kim , Daria J. Hazuda *, John W. Shiver **, and Antonello Pessi ¶
Departments of *Antiviral Research and **Vaccine and Biologics Research, and Office of the President, Merck Research Laboratories, West Point, PA 19486; ¶Istituto di Ricerche di Biologia Molecolare "P. Angeletti," 00040 Pomezia, Rome, Italy; and ||Cambridge Antibody Technology, Cambridge CB 16GH, United Kingdom
Contributed by Peter S. Kim, August 12, 2005
HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a "hot spot" for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential.<<
Cheers, Tuck |
