title: Antibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.
abstract: Broadly neutralizing antibodies PG9 and PG16 effectively neutralize 70 to 80% of circulating HIV-1 isolates. In this study, the neutralization abilities of PG9 and PG16 were further enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. A novel air-stable diazonium hexafluorophosphate reagent that allows for rapid, tyrosine-selective functionalization of proteins and antibodies under mild conditions was used to prepare a series of aplaviroc-conjugated antibodies, including b12, 2G12, PG9, PG16, and CD4-IgG. The conjugated antibodies blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency of the parent antibodies against nonresistant HIV-1 strains. Conjugation did not alter the pharmacokinetics of a model IgG in blood. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains. These results support this new approach to bispecific antibodies and offer a potential new strategy for combining HIV-1 therapies.
authors: Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
authors: Julia
authors: J
authors: Gavrilyuk
authors: Hitoshi
authors: H
authors: Ban
authors: Hisatoshi
authors: H
authors: Uehara
authors: Shannon J
authors: SJ
authors: Sirk
authors: Karen
authors: K
authors: Saye-Francisco
authors: Angelica
authors: A
authors: Cuevas
authors: Elise
authors: E
authors: Zablowsky
authors: Avinash
authors: A
authors: Oza
authors: Michael S
authors: MS
authors: Seaman
authors: Dennis R
authors: DR
authors: Burton
authors: Carlos F
authors: CF
authors: Barbas
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D016860:CD4 Immunoadhesins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D054659:Diketopiperazines; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D009500:Neutralization Tests; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D001565:Benzoates; D016860:CD4 Immunoadhesins; D054659:Diketopiperazines; D015483:HIV Antibodies; D018796:Immunoconjugates; D010879:Piperazines; D013141:Spiro Compounds; C499671:aplaviroc