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The Journal of Immunology, 2003, 171: 6251-6259.
Copyright © 2003 by The American Association of Immunologists

Activity and Safety of CTLA-4 Blockade Combined with Vaccines in Cynomolgus Macaques

Tibor Keler1,*, Ed Halk{ddagger}, Laura Vitale*, Tom O’Neill*, Diann Blanset*, Steven Lee2,{ddagger}, Mohan Srinivasan{ddagger}, Robert F. Graziano*, Thomas Davis3,{dagger}, Nils Lonberg{ddagger} and Alan Korman1,{ddagger}

Departments of * Preclinical Development and {dagger} Clinical Science, Medarex, Bloomsbury, NJ 08804; and {ddagger} Department of Research and Development, Medarex, Milpitas, CA 95035

The immune modulatory molecule CTLA-4 (CD152), through interactions with the B7 costimulatory molecules, has been shown to be a negative regulator of T cell activation in various murine model systems. Abs that block CTLA-4 function can enhance immune responses that mediate potent antitumor activity. However, CTLA-4 blockade can also exacerbate autoimmune disease. The safety and activity of anti-CTLA-4 Abs in primates has not been addressed. To that end, we generated human Abs against CTLA-4 using transgenic mice expressing human Ig genes. A high affinity Ab (10D1) that blocked the binding of CTLA-4 to the B7-1 and B7-2 ligands and had cross-reactivity with macaque CTLA-4 was chosen for further development. Administration of 10D1 to cynomolgus macaques significantly enhanced Ab responses to hepatitis surface Ag and a human melanoma cell vaccine. Anti-self Ab responses as measured by immunoassays using lysate from melanocyte-rich tissues were elicited in those animals receiving the melanoma cell vaccine and anti-CTLA-4 Ab. Remarkably, chronic administration of 10D1 did not result in measurable polyclonal T cell activation, significant alteration of the lymphocyte subsets, or induce clinically observable autoimmunity. Repeated dosing of the 10D1 did not elicit monkey anti-human Ab responses in the monkeys. These observations support the development of CTLA-4 blockade for human immunotherapy.




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