Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques.
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.
Keler
Tibor
T
Department of Preclinical Development, Medarex, Bloomsbury, NJ 08804, USA. tkeler@medarex.com
Halk
Ed
E
Vitale
Laura
L
O'Neill
Tom
T
Blanset
Diann
D
Lee
Steven
S
Srinivasan
Mohan
M
Graziano
Robert F
RF
Davis
Thomas
T
Lonberg
Nils
N
Korman
Alan
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D000914:Antibodies, Viral / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D015536:Down-Regulation / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D007166:Immunosuppressive Agents