In developing non-immunogenic chemotherapy drugs,ImmunoGen Inc. has devised a new way to potentially targetthose drugs to cancer cells: an antibody humanized through atechnique called resurfacing.
"Resurfacing leaves the original antibody framework intact bychanging only the surface-accessible regions of the antibody tomake it appear human," explained Walter Blattler,ImmunoGen's vice president of research.
In vitro cell culture tests have shown that the resurfacedmouse antibody linked to a small chemotherapy drug has thesame binding affinity as immunoconjugates made from nativeantibody and from antibodies humanized through grafting ofthe complementarity determining regions, or CDRs, responsiblefor high-affinity binding.
CDR grafting entails mounting the binding region to a humanframework so that the antibody appears human. However, theframework must be altered to bring the CDR into the correctconformation, a step that normally requires "many iterations"through computer modeling, said Mark Ratner, spokesman forthe Cambridge, Mass., company (NASDAQ:IMGN).
Resurfacing appears to be quicker and easier, Ratner said,because only four to nine regions of single amino acidsubstitutions are required, and the conformation does not haveto be adjusted.
Although CDR grafting is already subject to several patents,ImmunoGen believes it has a proprietary position withresurfacing, and has filed a patent application regarding thistechnique.
"Using a resurfaced antibody in our products obviates the needto pay certain license fees and may open up the possibility ofout-licensing rights to the technique to other companies,"Blattler said.
The company and its collaborators have filed a patentapplication on the use of resurfacing, which Ratner said couldhave broad utility in the humanization of monoclonalantibodies.
Thousands of antibodies are deemed therapeutically useful, hesaid, although there are still problems, including keeping themin circulation.
Non-immunogenic immunoconjugates are designed to permitrepeated dosing for long-term cancer treatment and otherapplications, said Mitchel Sayare, ImmunoGen's chairman andchief executive officer.
ImmunoGen is developing two small chemotherapy drugs totarget via monoclonal antibodies to tumors. The companyreceived a patent notice in September for the use ofmaytansine, which it is licensing from Takeda ChemicalIndustries of Japan. It is also developing immunoconjugateanalogs of CC-1065, which is too potent to be used inconventional chemotherapy but could be advantageous intumor "debulking" by delivering potency specifically to tumorcells.
ImmunoGen expects to enter clinical trials with resurfacedantibodies within 12 months, Ratner said. The company iscompleting animal tests with an immunoconjugate of CC-1065using well-characterized mouse antibody and would like to filean investigative new drug (IND) application with thiscompound first to explore how the drug behaves.
The mouse antibody is used in ImmunoGen's main drug,Oncolysin B, which is used to kill residual cancer cells duringpost-remission consolidation therapy.
Although small drugs under development would be candidatesfor use in relapsed patients initially, they might later beapproved for first-line therapy, Ratner said.
-- Nancy Garcia Associate Editor
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