Constrained bicyclic peptide delivery of toxin & immune agonists to solid tumors
Johanna Lahdenranta, PhD, Director, In Vivo Pharmacology, Bicycle Therapeutics
About this talk
We have developed tumor-targeted toxin conjugates (Bicycle toxin conjugates, BTCs) as well as tumor targeted immune cell agonists (TICAs™) based on constrained bicyclic peptides (Bicycles®) by linking toxins such as MMAE or Bicycles against costimulatory receptors (e.g. CD137) to those against tumor antigens (e.g. EphA2 or Nectin-4). EphA2-targeted Bicycle toxin conjugate BT5528 gives rise to rapid update into tumors and fast renal elimination followed by persistent toxin levels in tumors without prolonged exposure of parent drug in the vasculature. This fast in, fast out kinetics gave rise to more favorable toxicology findings in rats and monkeys than were observed with MEDI-547 in preclinical and clinical studies. BT5528 dosing is underway in Phase I/II study in patients with advanced solid tumors. Nectin-4 targeted CD137 TICA is a potent agonist that activates costimulatory receptors selectively in the presence of tumor cells. Treatment of tumor antigen -expressing tumors in immunocompetent mice with TICAs lead to profound reprogramming of the tumor immune microenvironment including increased T cell infiltration and increase in cytotoxic cell gene signature. This leads to cytotoxic T cell -dependent complete tumor regressions and resistance to tumor re-challenge. Despite fairly short plasma half-lives in mice (1 – 2h), intermittent dosing of TICAs is very effective indicating potential for a wide therapeutic index in humans. Cell line and patient derived tumor xenograft models as well as transgenic huCD137 syngeneic mouse tumor models have been instrumental in the preclinical development of BTCs and TICAs.
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