Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343

  • Clin Cancer Res. 2019 Oct 1;25(19):5878-5889. doi: 10.1158/1078-0432.CCR-18-3654.
Marlon J Hinner  1 ,  Rachida Siham Bel Aiba  2 ,  Thomas J Jaquin  2 ,  Sven Berger  2 ,  Manuela Carola Dürr  2 ,  Corinna Schlosser  2 ,  Andrea Allersdorfer  2 ,  Alexander Wiedenmann  2 ,  Gabriele Matschiner  2 ,  Julia Schüler  3 ,  Ulrich Moebius  2 ,  Christine Rothe  2 ,  Louis Matis  2 ,  Shane Anthony Olwill  1
Affiliations
  • 1. Research and Development, Pieris Pharmaceuticals GmbH, Freising, Germany. [email protected] [email protected].
  • 2. Research and Development, Pieris Pharmaceuticals GmbH, Freising, Germany.
  • 3. In Vivo Operations, Oncotest GmbH, Freiburg, Germany.
PMID: 31138587 DOI: 10.1158/1078-0432.CCR-18-3654
Abstract

Purpose: 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in Cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.

Experimental design: PRS-343 was generated by the genetic fusion of 4-1BB-specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys.

Results: PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB-expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of Cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.

Conclusions: PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule.See related commentary by Su et al., p. 5732.

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