Maytansinoids as Immunoconjugates
Rajeeva Singh, Ph.D., director of biochemistry at ImmunoGen (www.immunogen.com), adapted the magic bullet approach. His group focuses on the maytansinoids, highly potent cytotoxic agents that can be easily coupled to antibodies.
Since one would not anticipate that the conjugate molecule could work in a catalytic fashion, it is essential that compounds with extremely high potency be incorporated into the procedure. Many poisonous substances must be present in micromolar levels to exert significant cytotoxicity. Delivering such a high level of toxin to the cell is clearly impossible, precluding their use as immunotoxins. This requires that only the most potent candidates can be considered for this system.
Maytansinoids fit the bill, as these inhibitors of microtubular assembly boast IC50s in the subnanomolar range. The members of the maytansinoid family are bacterial compounds that are extensively modified to improve stability and solubility.
ImmunoGen chemists increased the stability of a disulfide linker by alkyl substitution, while a thioether conjugate allows a covalent attachment to the antibody.
In a model system of human colon cancer xenografts, the human antibody HuC242 coupled to a synthetic maytansinoid has effective killing power. The controls without antibody or applied to other cell lines that lack the target antigen, however, had little effect.
A surprising property of the system is a bystander effect by which the antibody-drug conjugate is seen to kill nontarget cells in close proximity to the tumor cell when challenged in vitro. When cells containing the antigen targeted by the HuC242 antibody are mixed with antigen-negative tumor cells, both tumor types are destroyed following treatment with the conjugate. This property could help to eliminate nearby tumor cells that have not taken up the drug.
Currently, ImmunoGen is moving the maytansinoid-antibody conjugates into the clinic through a collaboration with Genentec(www.gene.com). Using Herceptin conjugated with a noncleavable, thioether linker, a Phase I study of HER2 positive, metastatic breast cancer patients showed it was well-tolerated. Also, four out of 10 patients demonstrated an objective response. The study was reported at the recent “American Society of Clinical Oncology” meeting.
In another series of trials, patients were evaluated with ImmunoGen’s HuN901 antibody conjugate targeting multiple myeloma and CD56-expressing solid cancers as well as small-cell lung cancers. Once again, the drug was well tolerated, and several patients showed objective responses.
The antibody-maytansinoid conjugates with sterically hindered disulfide linkers appear to be an appealing and novel approach to the issue of malignancy. ImmunoGen is engaged in a number of clinical and preclinical programs in collaboration with Centocor(www.centocor.com), Biogen-Idec (www.biogen.com), Biotest(www.biotest.com), Genentech, and sanofi-aventis (www.sanofi-aventis.com).