Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities

• Published in: Antiviral research Vol. 74; no. 2; pp. 125 - 137
• Main Authors: Ji, Changhua, Brandt, Michael, Dioszegi, Marianna, Jekle, Andreas, Schwoerer, Stephan, Challand, Steven, Zhang, Jun, Chen, Yun, Zautke, Lisa, Achhammer, Gunthar, Baehner, Monika, Kroetz, Sandra, Heilek-Snyder, Gabrielle, Schumacher, Ralf, Cammack, Nick, Sankuratri, Surya
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.05.2007; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antiviral agents; Biological and medical sciences; CCR5; CCR5 Receptor Antagonists; Cell Fusion; Cell Line; Chemokine CCL5 - metabolism; Cricetinae; Drug Synergism; Entry inhibitor; Female; HIV; HIV - drug effects; HIV - physiology; Human immunodeficiency virus; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Medical sciences; Mice; Mice, Inbred BALB C; Monoclonal antibody; Pharmacology. Drug treatments; Receptors, CCR5 - immunology; Receptors, CCR5 - metabolism; Synergism; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Entry inhibitor; Monoclonal antibody; HIV; CCR5; Synergism; Immunopathology; Antiretroviral agent; Retroviridae; AIDS; Immune deficiency; Lentivirus; Biological activity; Infection; Virus; CCR5 chemokine receptor; Viral disease; Antiviral; Activity spectrum; Human immunodeficiency virus
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2006.11.003

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 μg/ml) and PBMC viral replication (IC 50 range: 0.02–0.04 μg/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, MIP1α and MIP1β 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.