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. 2003 Dec 1;171(11):6251-9.
doi: 10.4049/jimmunol.171.11.6251.

Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques

Tibor Keler  1 , Ed Halk, Laura Vitale, Tom O'Neill, Diann Blanset, Steven Lee, Mohan Srinivasan, Robert F Graziano, Thomas Davis, Nils Lonberg, Alan Korman
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Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques

"VSports app下载" Tibor Keler et al. J Immunol. .

Abstract

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 VSports手机版. 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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