| Autor: |
Cecile Geuijen, Alan Roberts, Kees Bol, Arpita Mondal, Wilfred E. Marissen, Liang-Chuan Wang, Paul Tacken, Patrick Mayes, Mark Throsby, Jeroen Elaissais-Schaap, Steef Engels |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl 3 (2020) |
| DOI: |
10.1136/jitc-2020-sitc2020.0814 |
| Popis: |
Background Only a fraction of cancer patients benefit from currently available immune checkpoint inhibitors (ICI). Attempts to improve efficacy of ICI by combining with costimulatory receptor agonists such as CD137 (4-1BB) have led to greater anti-tumor activity preclinically but have shown systemic toxicity in the clinic. MCLA-145 is a human CD137xPD-L1 bispecific common light chain antibody (bAb), identified through functional screening of agonist and ICI bAb combinations. Further, MCLA-145 can overcome Treg and macrophage suppression to potently activate T cells in these immune suppressive conditions. In two ICI insensitive xenograft models, MCLA-145 demonstrated good anti-tumor activity and CD8+ T cells were enriched in tumors post treatment (indicative of intratumor expansion and recruitment). No signs of GvHD were observed in mice following treatment with MCLA-145 in contrast to that seen in animals treated with other ICI mAbs. Methods The EC30 from an in vitro T cell transactivation assay based on IFNg was used as an estimate of the MABEL for MCLA-145. A 2 compartment PK model coupled to a target-mediated drug disposition component was generated based on the available cynomolgus monkey PK data. Results Repeated doses of MCLA-145 up to 100 mg/kg/wk in cynomolgus monkeys were well tolerated without major adverse effects, and dose-dependent increases in serum MCLA-145 concentrations were observed. Following allometric scaling, the model was used to predict exposure in humans following MCLA-145 IV given over 2-hours every 2 weeks, including the starting dose for the FIH trial. Conclusions Conditional activation of CD137 signaling by MCLA-145, triggered by a neighboring target cell expressing of PD-L1, may provide both improved efficacy and safety. MCLA-145 is currently undergoing clinical investigation (NCT03922204). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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