SCDT-39. NANOBIOCONJUGATES CROSSING BBB FOR DELIVERY OF CHECKPOINT INHIBITORS AND ACTIVATION OF LOCAL BRAIN TUMOR IMMUNE SYSTEMS FOR GLIOMA TREATMENT

摘要

Glioblastoma multiforme (GBM) still has limited treatment options. We introduce a new generation of nanobioconjugates that deliver anti-CTLA-4 and/or anti-PD-1 antibodies through blood-brain barrier (BBB) and activate local brain tumor immune response directed against GBM.METHODSImmuno-nanobioconjugates (INC) based on natural polymer, poly b(L-malic acid) (P) and crossing BBB were synthesized: P/PEG/msTfR/anti-CTLA-4 and P/PEG/msTfR-pTfR/anti-PD-1 (MsTfR and pTfR are anti-transferrin receptor antibody and peptide, respectively). Physico-chemical, pharmacological, and toxicological parameters of INCs were determined. Syngeneic GL261 glioma cells were intracranially inoculated into C57/BL mice. Treatment groups were injected 5 times I.V. with either PBS, or anti-PD1 and anti-CTLA4 as a control, or polymer conjugated to anti-PD1(P/PD1), anti-CTLA-4 (P/CTLA-4) or a combination (P/CTLA-4+P/PD-1) at 5 or 10 mg/kg, with a new premedication regimen to reduce immunotoxicity.