Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model.

Media type: E-Article

Title: Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model

Contributor: Hepp, Julia; Link, Alexander; Fiedler, Ulrike; Reichen, Christian; Metz, Clara; Titz, Alexander; Tosevski, Ivana; Juglair, Laurent; Schildknecht, Patricia; Kaufmann, Yvonne; Fontaine, Simon; Bessey, Ralph; Arany, Zita; Zitt, Christof; Dawson, Keith M.; Steiner, Daniel; Snell, Dan; Levitsky, Victor; Stumpp, Michael T.

imprint: American Society of Clinical Oncology (ASCO), 2017

Language: English

DOI: 10.1200/jco.2017.35.15_suppl.e14626

ISSN: 0732-183X; 1527-7755

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: e14626 Background: Urelumab (BMS-663513) is a humanized monoclonal antibody binding to CD137 which, upon Fc-clustering, leads to activation of T-cells. Urelumab is currently in Phase 2 clinical development and has been reported to cause significant hepatotoxicities (around 15% Grade ≥2 ALT and AST elevation) when given as infusion every 3 weeks at doses ≥0.3 mg/kg. Currently ongoing clinical trials report decreased systemic toxicity but limited efficacy at lower doses of urelumab. We hypothesized that more effective triggering of CD137 without associated systemic toxicity may be achieved by targeting a CD137 agonistic engager without Fc to fibroblast activation protein (FAP) which is abundantly expressed in the stroma of many solid tumors. To achieve this, a targeted molecule belonging to the DARPin family of binding proteins was composed of one FAP- and two CD137-binding domains in a “beads on a string” format and tested in a mouse model with human PBMCs. Methods: Human PBMCs were used to reconstitute the immune system in NOG mice implanted subcutaneously with HT-29 human colon cancer cells. Mice were monitored for survival, body weight, and tumor size during the treatment phase of two weeks. Results: None of the mice in the control group died and no significant body weight loss was observed. Six of ten (60%) mice in the CD137 antibody group showed strong signs of graft vs. host disease and either died or reached the termination criterion of ≥20% body weight loss and were sacrificed. One of 30 (3%) mice died in the DARPin drug candidate groups but none of the animals showed body weight loss of ≥20% (p < 0.001, Log-rank test). Tumor growth inhibition was comparable for all treatment groups (around 20-30% at Day 18, p < 0.05 vs. control, Mann Whitney Test). Conclusions: This study confirms the hypothesis that systemic toxicities caused by the urelumab mode of action can be circumvented by FAP-targeting of a CD137 agonistic DARPin drug candidate while achieving comparable tumor growth inhibition. Consequently, higher clinical doses of tumor stroma-targeted agonistic DARPin drug candidates might be possible, and may result in stronger tumor growth inhibition.

Access State: Open Access

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