1. Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
- Author
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Manuela Carola Dürr, Sven Berger, Alexander Wiedenmann, Christine Rothe, Rachida Siham Bel Aiba, Ulrich Moebius, Corinna Schlosser, Marlon Hinner, Julia Schüler, Gabriele Matschiner, Louis Matis, Andrea Allersdorfer, Shane Olwill, and Thomas Jaquin
- Subjects
0301 basic medicine ,Cancer Research ,T cell ,T-Lymphocytes ,Lymphocyte Activation ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Neoplasms ,Antibodies, Bispecific ,medicine ,Animals ,Humans ,biology ,Chemistry ,CD137 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Humanized mouse ,biology.protein ,Cancer research ,Antibody ,Ex vivo - 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
- Published
- 2018