Optimization and Therapeutic Activity of Liposome-Conjugated Monoclonal Antibodies Against the ErbB family of Receptor Tyrosine Kinases: First Step in the Development of Therapeutic Antibody/Liposomal Anticancer Drug Combinations
Gigi N.C. Chiu,
Troy O. Harasym,
Paul G. Tardi,
Marcel B. Bally,
Dawn N. Waterhouse.
Humanized monoclonal antibodies specific for two ErbB family members, an anti-EGFR (HER1) antibody (cetuximab) and an anti-HER2 antibody (trastuzumab), are proved to be therapeutically important. In this report, we have attempted to design long circulating liposome carriers that have covalently attached, therapeutically active monoclonal antibodies (mAb) specific for EGFR or HER2. Two issues that were resolved here concerned: 1) the use of whole mAb in preparing liposomal conjugates exhibiting extended circulation lifetime and improved mAb delivery to tumors, and 2) the selection of a coupling strategy that did not influence the anti-cancer activity of the conjugated therapeutic antibody. Unlike previous studies contemplating the use of antibodies to target liposomes, the rationale for the studies described in this report was based on the potential that such liposomes could be developed as a versatile approach to deliver the associated antibody/drug combinations to sites of tumor growth. We have demonstrated that strategies which minimized the accessibility of Fc region of the conjugated mAb were useful in reducing plasma elimination of the mAb-liposome conjugates. In particular, Fc exposure could be reduced by conjugating mAb via carbohydrate moieties, which resulted in improved circulation longevity and a five-fold increase in tumor liposomal lipid levels compared to those observed for liposomes prepared with mAb conjugated through amine thiolation. Alternatively, amine conjugation of mAb to the poly(ethylene glycol) terminus resulted in circulation kinetics comparable to those of non-targeted liposomes. Using the later approach, conjugation of the therapeutically active mAb, trastuzumab, did not substantially compromise the anti-tumor activity of the mAb as measured in a human MDA-MB-435/LCC6HER2 (LCC6HER2) breast cancer xenograft model. These results indicate the potential of such liposomal formulations for use in combination with encapsulated anticancer drugs that would act synergistically with mAb against ErbB family members.
Keywords: Liposomes, Therapeutic antibodies, Combination therapy
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