Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.

The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents.

Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation.

Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.

Synthesis, in vitro kinetics, and in vivo studies on protein conjugates of AZT: evaluation as a transport system to increase brain delivery.

Our method to increase the delivery of polar drugs to the central nervous system is via drug-protein conjugates with proteins that interact with and cross brain capillary endothelial cells. As a model for drugs containing a reactive hydroxyl group, AZT was conjugated via a succinate linker to two such protein carriers, the highly cationic histone H1 and an anti-transferrin receptor antibody, OX-26. The protein carriers were selected on the basis of their ability to interact with brain capillary endothelial cells by absorptive or receptor-mediated events, respectively. An in vitro pH profile of the rate of AZT release indicated that the observed hydrolysis proceeds by a specific base-catalysis mechanism. At 37 degrees C, the release of AZT proceeded at a rate approximately 10-fold faster (Kobs approximately 8 x 10(-4) min-1) than expected for a simple ester (AZT succinate; Kobs approximately 1.25 x 10(-4) min-1). Using simple model systems, product analysis revealed that intramolecular cyclization of the succinate linker accounts for the observed rate enhancement. Drug delivery in vivo was assessed using immunohistochemical techniques and quantitative brain uptake measurements with singly and doubly labeled AZT-OX-26 conjugates. Immunohistochemical staining of brain sections showed the colocalization of AZT and OX-26 in the brain vasculature. Therefore, drug can be linked to the antibody without affecting the targeting property of the antibody. Furthermore, an in vivo time course using radiolabeled conjugate showed that AZT is delivered to the brain capillaries but is not transported into the brain parenchyma with the antibody.(ABSTRACT TRUNCATED AT 250 WORDS)