Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities.
To identify monoclonal antibodies (mAbs) with high potency and novel recognition sites, more than 25,000 of mouse hybridomas were screened and 4 novel anti-human CCR5 mAbs ROAb12, ROAb13, ROAb14, and ROAb18 showing potent activity in cell-cell fusion (CCF) assay were identified. These mAbs demonstrated potent antiviral activities in both single-cycle HIV infection (IC(50) range: 0.16-4.3 microg/ml) and PBMC viral replication (IC(50) range: 0.02-0.04 microg/ml) assays. These potent antiviral effects were donor-independent. All 4 mAbs were also highly potent in the PhenoSense assay against 29 HIV isolates covering clade A through G. In all antiviral assays, these mAbs showed potency superior to the previously reported mAb 2D7 in side-by-side comparison studies. All 4 mAbs were also fully active against viruses resistant to HIV fusion inhibitor enfuvirtide and CCR5 antagonist maraviroc. Although ROAb12, ROAb14, and ROAb18 inhibited RANTES, MIP1alpha and MIP1beta binding and cell activation, the other novel mAb ROAb13 was inactive in inhibiting cell activation by these three ligands. Furthermore, highly synergistic antiviral effects were found between mAb ROAb13 and 2D7 or ROAb12. In addition, none of these mAbs showed agonist activity or caused internalization of the CCR5 receptor.
Ji
Changhua
C
Department of Viral Diseases, Roche Palo Alto, 3411 Hillview Avenue, Palo Alto, CA 94304, USA. Changhua.ji@roche.com
Brandt
Michael
M
Dioszegi
Marianna
M
Jekle
Andreas
A
Schwoerer
Stephan
S
Challand
Steven
S
Zhang
Jun
J
Chen
Yun
Y
Zautke
Lisa
L
Achhammer
Gunthar
G
Baehner
Monika
M
Kroetz
Sandra
S
Heilek-Snyder
Gabrielle
G
Schumacher
Ralf
R
Cammack
Nick
N
Sankuratri
Surya
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D002459:Cell Fusion; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D006224:Cricetinae; D004357:Drug Synergism; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D019713:Receptors, CCR5 / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; C493277:MAPKAP1 protein, human; D019713:Receptors, CCR5