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PD-1 Blockade in Rhesus Macaques: Impact on Chronic Infection and Prophylactic Vaccination

Adam C. Finnefrock^1,*, Aimin Tang^*, Fengsheng Li^*, Daniel C. Freed^*, Meizhen Feng, Kara S. Cox^*, Kara J. Sykes^*, James P. Guare, Michael D. Miller, David B. Olsen, Daria J. Hazuda, John W. Shiver, Danilo R. Casimiro^* and Tong-Ming Fu^1,*

^* Vaccine Basic Research, Antiviral Research, Medicinal Chemistry, and Infectious Disease, Merck Research Laboratories, West Point, PA 19486

Programmed Cell Death 1 (PD-1) plays a crucial role in immunomodulation. Binding of PD-1 to its ligand receptors down-regulates immune responses, and published reports suggest that this immune modulation is exploited in cases of tumor progression or chronic viral infection to evade immune surveillance. Thus, blockade of this signal could restore or enhance host immune functions. To test this hypothesis, we generated a panel of mAbs specific to human PD-1 that block PD ligand 1 and tested them for in vitro binding, blocking, and functional T cell responses, and evaluated a lead candidate in two in vivo rhesus macaque (Macaca mulatta) models. In the first therapeutic model, chronically SIV-infected macaques were treated with a single infusion of anti-PD-1 mAb; viral loads increased transiently before returning to, or falling below, pretreatment baselines. In the second prophylactic model, naive macaques were immunized with an SIV-gag adenovirus vector vaccine. Induced PD-1 blockade caused a statistically significant (p < 0.05) increase in the peak percentage of T cells specific for the CM9 Gag epitope. These new results on PD-1 blockade in nonhuman primates point to a broader role for PD-1 immunomodulation and to potential applications in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Adam C. Finnefrock or Dr. Tong-Ming Fu, WP16-205, Vaccine Basic Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486. E-mail address: adam_finnefrock{at}merck.com or tong-ming_fu{at}merck.com

² Abbreviations used in this paper: PD-1, programmed cell death 1; PD-L1, PD-1 ligand 1; PD-L2, PD-1 ligand 2; LCMV, lymphocytic choriomeningitis virus; SPR, surface plasmon resonance; ART, antiretroviral therapy; ICS, intracellular cytokine staining; RAMA, rhesus anti-mouse IgG Ab.

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