Synergistic Neutralization of Simian-Human Immunodeficiency Virus SHIV-vpu+ by Triple and Quadruple Combinations of Human Monoclonal Antibodies and High-Titer Anti-Human Immunodeficiency Virus Type 1 Immunoglobulins

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J Virol, April 1998, p. 3235-3240, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Synergistic Neutralization of Simian-Human Immunodeficiency Virus SHIV-vpu⁺ by Triple and Quadruple Combinations of Human Monoclonal Antibodies and High-Titer Anti-Human Immunodeficiency Virus Type 1 Immunoglobulins

An Li,¹^,² Hermann Katinger,³ Marshall R. Posner,²^,⁴ Lisa Cavacini,²^,⁴ Susan Zolla-Pazner,⁵ Miroslaw K. Gorny,⁵ Joseph Sodroski,²^,⁶ Ting-Chao Chou,⁷ Timothy W. Baba,¹^,²^,⁸ and Ruth M. Ruprecht¹^,²^,^*

Laboratory of Viral Pathogenesis¹ and Division of Human Retrovirology,⁶ Dana-Farber Cancer Institute, and Harvard Medical School,² Boston, Massachusetts 02115; Institute of Applied Microbiology, University of Agriculture, A-1190 Vienna, Austria³; Division of Hematology and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215⁴; Research Center for AIDS and HIV Infection, Veterans Affairs Medical Center, New York, New York 10010⁵; Laboratory of Preclinical Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021⁷; and Division of Newborn Medicine, Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts 02111⁸

Received 25 August 1997/Accepted 18 December 1997

We have tested triple and quadruple combinations of human monoclonal antibodies (MAbs), which are directed against variousepitopes on human immunodeficiency virus type 1 (HIV-1) envelopeglycoproteins, and a high-titer anti-HIV-1 human immunoglobulin(HIVIG) preparation for their abilities to neutralize a chimericsimian-human immunodeficiency virus (SHIV-vpu⁺). This virus encodes the HIV-1 strain IIIB env, tat, rev, andvpu genes. The quantitative nature of the Chou-Talalay method(Adv. Enzyme Regul. 22:27-55, 1984) allows ranking of variouscombinations under identical experimental conditions. Of all triplecombinations tested, the most potent neutralization was seen withMAbs 694/98D plus 2F5 plus 2G12 (directed against domains on V3,gp41, and gp120, respectively) as measured by the total MAb concentrationrequired to reach 90% neutralization (90% effective concentration[EC₉₀], 2.0 µg/ml). All triple combinations involving MAbs and/orHIVIG that were tested yielded synergy with combination indexvalues of <1; the dose reduction indices (DRIs) ranged from 3.1to 26.2 at 90% neutralization. When four MAbs (the previous threeplus MAb F105, directed against the CD4 binding site) were combined,higher neutralization potency (EC₉₀, 1.8 µg/ml) and a higher degreeof synergy compared to any triple combination were seen. The meanDRIs of the quadruple combination were approximately twice thatof the most synergistic triple combination. We conclude that humanMAbs targeting different HIV-1 envelope glycoprotein epitopesexhibit strong synergy when used in combination, a fact that couldbe exploited clinically for passive immunoprophylaxis againstHIV-1.

^* Corresponding author. Mailing address: Laboratory of Viral Pathogenesis, Dana-Farber Cancer Institute, 44 Binney St., Boston,MA 02115. Phone: (617) 632-3719. Fax: (617) 632-3112. E-mail:ruth_ruprecht{at}dfci.harvard.edu.

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