Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study.
The immune-stimulatory properties of anti-CD134 (OX40) antibodies have been well documented in rodents, including their ability to enhance antitumor immunity. In this study, an anti-OX40 antibody (Ab) known to costimulate monkey T cells in vitro, was infused into rhesus macaque monkeys during immunization with the simian immunodeficiency virus protein, gp130. The draining lymph nodes from immunized monkeys treated with anti-OX40 were enlarged compared with immunized monkeys injected with mouse Ig. Anti-OX40-treated monkeys had increased gp130-specific Ab titers, and increased long-lived T-cell responses, compared with controls. There were no overt signs of toxicity in the anti-OX40-treated monkeys. The encouraging immune-stimulatory effects led to the good manufacturing practice production of an anti-OX40 Ab for clinical trials in cancer patients. A detailed toxicology study was performed with anti-OX40 in nonhuman primates. Three groups of 8 monkeys received anti-OX40 at 1 of 3 dose levels (0.4, 2.0, and 10 mg/kg) and a control group received saline. No clinical toxicity was observed, but acute splenomegaly and enlarged gut-associated lymph nodes were observed in the anti-OX40-treated animals; splenomegaly and lymphadenopathy resolved by day 28. These studies demonstrate the immune-stimulatory properties and safety of anti-OX40 in primates and provide a strong scientific rationale to pursue clinical trials in humans.
Weinberg
Andrew D
AD
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 5F40, Portland, OR 97213, USA. andrew.weinberg@providence.org
Thalhofer
Colin
C
Morris
Nick
N
Walker
Joshua M
JM
Seiss
Donald
D
Wong
Scott
S
Axthelm
Michael K
MK
Picker
Louis J
LJ
Urba
Walter J
WJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002452:Cell Count; D005260:Female; D015686:Gene Products, env / Q000276:immunology; D006801:Humans; D006965:Hyperplasia; D016233:Immunotherapy, Active / Q000379:methods*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009929:Organ Size / Q000187:drug effects; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000906:Antibodies; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015686:Gene Products, env; D053262:Receptors, OX40; C078684:simian immunodeficiency virus gp130