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Design, Construction, and In Vitro Analyses of Multivalent Antibodies

Kathy Miller^1,*, Gloria Meng, Jun Liu, Amy Hurst, Vanessa Hsei^¶, Wai-Lee Wong, Rene Ekert^||, David Lawrence, Steven Sherwood^*, Laura DeForge, Jacques Gaudreault^¶, Gilbert Keller^||, Mark Sliwkowski, Avi Ashkenazi and Leonard Presta^*

Departments of ^* Immunology, Assay and Automation Technology, Pharmaceutical Research and Development, Molecular Oncology, ^¶ Clinical and Experimental Pharmacology, and ^|| Toxicology, Genentech, Inc., South San Francisco, CA 94080

Some Abs are more efficacious after being cross-linked to form dimers or multimers, presumably as a result of binding to and clustering more surface target to either amplify or diversify cellular signaling. To improve the therapeutic potency of these types of Abs, we designed and generated Abs that express tandem Fab repeats with the aim of mimicking cross-linked Abs. The versatile design of the system enables the creation of a series of multivalent human IgG Ab forms including tetravalent IgG1, tetravalent F(ab')₂, and linear Fab multimers with either three or four consecutively linked Fabs. The multimerized Abs target the cell surface receptors HER2, death receptor 5, and CD20, and are more efficacious than their parent mAbs in triggering antitumor cellular responses, indicating they could be useful both as reagents for study as well as novel therapeutics.

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