Coiled-coil based drug-free macromolecular therapeutics: In vivo efficacy

We evaluated a new concept in cancer therapy, coiled-coil mediated induction of apoptosis in Raji B cells, for treatment of human B-cell lymphoma in a preclinical animal model. The system is composed of a pair of complementary coiled-coil peptides, CCE and CCK, forming antiparallel heterodimers; Fab′ fragment of the 1F5 anti-CD20 antibody; and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. One peptide is conjugated to the Fab′ fragment (Fab′-CCE), the other is conjugated in multiple grafts to polyHPMA (CCK-P; P is the HPMA copolymer backbone). Intravenous administration of Fab′-CCE conjugate, followed by the administration of CCK-P produced long-term survivors in SCID (C.B.-17) mice bearing human B-lymphoma xenografts. The rationale of the design is the absence of low molecular weight drugs and the fact that crosslinking of CD20 at B-cell surface results in apoptosis. This approach creates a new paradigm for manipulating molecular recognition principles in the design of improved cancer treatment.

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