Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
Potency and broadness of neutralization of HIV-1 by alpha-V3 MAbS is enhanced by synergy with CD4 and cell killing with alpha-CD3 MAbS.
Int Conf AIDS. 1992 Jul 19-24;8(1):Mo13 (abstract no. MoA 0043). Unique Identifier : AIDSLINE ICA8/92400003 Potts B; Wu Y; Field K; Paradis T; Higgins P; White-Scharf M; Posner M; Cavacini L; Herlihy W; Repligen Corporation, Cambridge, MA.
Abstract:
OBJECTIVE: Identify ways to increase the potency and broaden the reactivity of HIV-1 neutralizing reagents to the V3 loop and the CD4 binding domain of the HIV-1 gp120 envelope. METHODS: Broadly neutralizing alpha-V3 MAbs and alpha-CD4 binding domain reagents have been evaluated individually, in combination to demonstrate synergy and, chemically coupled to an alpha-CD3 antibody to demonstrate CTL-heteroconjugate-mediated cytotoxicity of HIV infected cells. The Infectivity Reduction Assay (IRA) which measures the ability of a reagent to block HIV virus replication 100% was used to evaluate 3 lab adapted isolates, 4 field isolates and 4 monocyte tropic field isolates. The alpha-V3 MAbs used were 59.1, 83.1 and 58.2, the alpha-CD4 binding domain reagents were the huMAb F105 and sCD4. Virus was titered in the presence and absence of antibody (10 micrograms) CD4 (5 micrograms) or heteroconjugate (1 microgram) then inoculated into the CEM-SS or PBLs. CTLs were added to the heteroconjugate (HC) assay at an E:T ratio of 3:1. Virus replication was monitored by the RT assay using (32)PdTTTP. RESULTS: The alpha-V3 MAbs 83.1 and 58.2 are potent and broadly neutralizing antibodies and although 59.1 is broadly reactive by peptide mapping it is a weak neutralizing Ab and type specific for MN and IIIB. When F105 or CD4 were combined with these MAbs the potency of neutralization increased 10 and 100 fold respectively when tested on MN but only CD4 synergized with 83.1 and 58.2 on field isolates increasing potency 100 fold. Although the potency of the V3 MAbs were increased substantially the reactivity to additional HIV isolates did not occur. In comparison, the 59.1-alpha-CD3 HC increased potency 100 fold and broadness 10 fold suggesting that HC mediated neutralization only requires binding for cytotoxicity to occur. CONCLUSIONS: V3 directed MAbs (59.1, 83.1, 58.2) and CD4 binding domain reagents (F105, CD4) are capable of neutralizing individually but when combined synergize to increase potency 100 fold. The most potent and broadly reactive combinations were 83.1 or 58.2 plus CD4. When a V3 MAb is used to make a bispecific heteroconjugate cross-linked to an alpha-CD3 Ab both potency and reactivity of the V3 MAb increased significantly.
Keywords: Antibodies, Monoclonal/*IMMUNOLOGY Antibody Specificity Antibody-Dependent Cell Cytotoxicity Antigens, CD4/*IMMUNOLOGY Antigens, Differentiation, T-Lymphocyte/*IMMUNOLOGY Binding Sites Cells, Cultured Human HIV Antibodies/IMMUNOLOGY HIV Envelope Protein gp120/*IMMUNOLOGY HIV-1/*IMMUNOLOGY/PHYSIOLOGY Neutralization Tests Peptide Fragments/*IMMUNOLOGY Receptors, Antigen, T-Cell/*IMMUNOLOGY T-Lymphocytes, Cytotoxic/IMMUNOLOGY Virus Replication ABSTRACT 921230
M92C5344
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
