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

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. 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.

• Authors: Tibor Keler, Ed Halk, Laura Vitale, Tom O'Neill, Diann Blanset, Steven Lee, Mohan Srinivasan, Robert F Graziano, Thomas Davis, Nils Lonberg, Alan Korman
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 11 Pg. 6251-9 (Dec 01 2003) ISSN: 0022-1767 [Print] United States
• PMID: 14634142 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Blocking
• Antibodies, Monoclonal
• Antibodies, Viral
• Antigens, CD
• Antigens, Differentiation
• CTLA-4 Antigen
• CTLA4 protein, human
• Cancer Vaccines
• Ctla4 protein, mouse
• Hepatitis B Surface Antigens
• Hepatitis B Vaccines
• Immunosuppressive Agents

Topics

• Adjuvants, Immunologic (administration & dosage, pharmacology)
• Animals
• Antibodies, Blocking (adverse effects, chemistry, pharmacology)
• Antibodies, Monoclonal (adverse effects, chemistry, pharmacology)
• Antibodies, Viral (biosynthesis)
• Antigens, CD
• Antigens, Differentiation (immunology)
• CTLA-4 Antigen
• Cancer Vaccines (administration & dosage, immunology, pharmacology)
• Down-Regulation (immunology)
• Drug Synergism
• Female
• Hepatitis B Surface Antigens (immunology)
• Hepatitis B Vaccines (administration & dosage, immunology, pharmacology)
• Humans
• Immunosuppressive Agents (antagonists & inhibitors, immunology)
• Macaca fascicularis
• Male
• Mice
• Mice, Transgenic