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[Proc Amer Assoc Cancer Res, Volume 45, 2004]


Experimental and Molecular Therapeutics 6: Novel Delivery Strategies

Abstract #627

Controlling the location of drug attachment in antibody-drug conjugates

Stephen Alley, Michael Sun, Michael Torgov, Kevin Beam, Kevin Hamblett, Charles Cerveny, Joseph Francisco, Nathan Ihle and Peter Senter

Seattle Genetics, Inc., Bothell, WA

In preparing antibody-drug conjugates (ADCs) for cancer therapy, particular attention has been focused on monoclonal antibody (mAb) specificity, drug potency, and linker technology. However, the sites and extent of mAb modification have not been investigated in detail and may play critical roles in immunoreactivity, biological distribution, toxicity, and efficacy. The most common methods for attaching drugs to mAbs utilize cysteines, lysines, and carbohydrates. The advantage of using endogenous cysteines for modification is that since only a few of them are chemically reactive, a great degree of control over the site of drug attachment is possible. Human IgG1 mAbs have 4 reducible interchain disulfides, yielding 8 potential sites for drug attachment. A previously described ADC, cAC10-valine-citrulline-MMAE, was prepared that had 8 monomethylauristatin E (MMAE) molecules per mAb. This ADC was highly effective in treating CD30 positive hematologic malignancies in a xenotransplant setting. We have recently shown that ADCs with fewer drugs per mAb are just as effective and provide a better therapeutic window. Consequently, we explored several methods for preparing ADCs with fewer drugs/mAb. These conjugates are mixtures of partially drug-loaded isomers, and as a result, we developed methods to map the sites of drug attachment on the antibody. Here, we describe partial reduction methods for making ADCs with auristatins that allow for control over the distribution of molecular species. We describe analytical methods for determining the isomeric composition of these ADCs, and show that some of the reduction methods lead to ADCs with up to 90% isomeric purity. The ADCs described here are highly homogeneous, have retained binding activities, and have potent in vitro and in vivo activities against CD30 positive tumors.







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Cancer ResearchClinical Cancer Research
Cancer Epidemiology Biomarkers & PreventionMolecular Cancer Therapeutics
Molecular Cancer ResearchCancer Prevention Research
Cancer Prevention Journals PortalCancer Reviews Online
Annual Meeting Education BookMeeting Abstracts Online
Copyright © 2004 by the American Association for Cancer Research.