In vitro: Ipilimumab, is a fully humanized IgG1k monoclonal antibody produced by recombinant DNA technology in a CHO mammalian cell expression system, binding with high affinity to the extracellular domain of human (and Cynomolgus monkey) CTLA-4, and acting as an inhibitor of its complex functions. This essentially results in T-cell activation and proliferation, and in lymphocyte infiltration leading to tumor cell death. However, the enhancement of T effector cell function, combined with the inhibition of CD4+ Treg and CD8+ suppressive cell types, are considered essential for mediating the full therapeutic effects of ipilimumab. Ipilimumab can improve ATC proliferation, enhance the BiAb-mediated tumor-specific cytotoxicity, and increase cytokine synthesis, while it attenuates Treg activity as shown by decreased level of IL-10 secretion and reduced Treg population. Ipilimumab and nivolumab treatments could collaboratively enhance effector and memory T cell responses without inappropriately activating naive T cells.
In vivo: Ipilimumab is shown in phase III clinical trials to have a survival benefit in metastatic melanoma that is durable in 10% to 20% of patients. Conceivably, the main adverse effects of ipilimumab are autoimmunein nature. Ipilimumab enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells (Treg).
|Preparation method||Add ipilimumab at the initiation of ATC expansion cultures from healthy donors at various concentrations ranging from 0 to 50 μg/mL. ATC(activated T cells) are harvested on day 14, armed with EGFRBi or CD20Bi, and co-cultured at 25:1 E:T(effector:target) ratio for 18 hours with EGFR positive pancreatic cancer cell line (COLO356/FG) or 4 hours with CD20 positive Burkitt's lymphoma cell line (Daudi) for cytotoxicity assay. BiAb-mediated tumor specific cytotoxicity is measured by 51Cr release assay.|
|Concentrations||0, 0.5, 5.0, and 50 μg/mL|
|Incubation time||14 days|
|Animal models||Purpose-bred cynomolgus monkeys|
|Dosages||3 mg/kg or 10 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
Antonia SJ, et al. Lancet Oncol. 2016 Jul;17(7):883-895. PMID: 27269741.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Robert C, et al. N Engl J Med. 2015 Jun 25;372(26):2521-32. PMID: 25891173.
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