With the FDA's recent approval of Adcetris for the treatment of Hodgkin Lymphoma and Kadcyla for the treatment of metastatic breast cancer, antibody drug conjugates (ADCs) have emerged as a new option for refractive cancer chemotherapy. ADCs utilize the targeting specificity of an antibody to deliver their potent, cytotoxic cargos selectively to cancerous tumors, providing efficacious treatment with an improved therapeutic index. However, conventional conjugation chemistries used in ADC production result in significant bioconjugate heterogeneity. These complex mixtures complicate analyses and do not easily allow for optimization of pharmacokinetic profiles. Hydrolytic instability of conventionally-prepared conjugates is also potentially problematic, leading to unexpected loss of drug payload in serum prior to tumor targeting. We have begun to address these issues using improved site-specific bioorthogonal conjugation methods and improved coupling chemistries.SMARTagTM (Specific Modifiable Aldehyde Recombinant Tag) technology developed at Redwood Bioscience is being used to produce homogeneous, semisynthetic ADCs. We utilize a genetically encoded formylglycine (FGly) 'aldehyde-tag' together with a newly developed Hydrazinyl-Iso-Pictet-Spengler (HIPS) carbon-carbon bond forming reaction to create highly stable, site-specifically modified bioconjugates. We will be presenting the novel HIPS conjugation strategy and its application to bioconjugate production, including generation and subsequent analysis of site-specifically modified ADCs.

Hydrazinyl-Iso-Pictet-Spengler (HIPS) ligation as a novel method for the generation of highly stable, site-specifically modified antibody drug conjugates

247th National Meeting (2014)

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