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

• DOI: 10.1158/1078-0432.c.6528768
• Publication Date: 2023-04-01T09:06:54Z
• Authors: Marlon J. Hinner; Rachida Siham Bel...; Thomas J. Jaquin; Sven Berger; Manuela Carola Dürr; Corinna Schlosser; Andrea Allersdorfer; Alexander Wiedenmann; Gabriele Matschiner; Julia Schüler; Ulrich Moebius; Christine Rothe; Louis Matis; Shane Anthony Olwill
• Keywords: CD137; Humanized mouse

<div>AbstractPurpose:<p>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, 4-1BB/HER2 bispecific molecule. PRS-343 designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering activation.</p>Experimental Design:<p>PRS-343 was generated the genetic fusion 4-1BB–specific Anticalin proteins variant trastuzumab with an engineered IgG4 isotype. Its activity characterized using panel <i>in vitro</i> assays humanized mouse models. The safety assessed <i>ex vivo</i> human cell toxicity study cynomolgus monkeys.</p>Results:<p>PRS-343 targets HER2 high affinity binds both simultaneously. 4-1BB–expressing T cells are efficiently costimulated when incubated presence cancer expressing HER2, as evidenced increased production proinflammatory cytokines (IL2, GM-CSF, TNFα, IFNγ). In model engrafted HER2-positive SK-OV-3 tumor peripheral blood mononuclear cells, leads growth inhibition dose-dependent increase tumor-infiltrating lymphocytes. IND-enabling studies, found be well tolerated, no overt relevant drug-related toxicologic findings.</p>Conclusions:<p>PRS-343 facilitates tumor-localized targeting engagement 4-1BB. This approach has potential provide more localized activation immune system higher efficacy reduced compared monospecific approaches. reported data led initiation phase I clinical trial this first-in-class molecule.</p><p><i>See related commentary Su et al., p. 5732</i></p></div>