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Research Articles: Therapeutics, Targets, and Development

Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index

Seattle Genetics, Inc., Bothell, Washington

Requests for reprints: Kristine M. Kim, Seattle Genetics, Inc., 21823 30th Drive Southeast, Bothell, WA 98021. Phone: 425-527-4644; Fax: 425-527-4609; E-mail: kkim{at}seagen.com.

Abstract

An anti-CD70 antibody conjugated to monomethylauristatin F (MMAF) via a valine-citrulline dipeptide containing linker has been shown previously to have potent antitumor activity in renal cell cancer xenograft studies. Here, we generated a panel of humanized anti-CD70 antibody IgG variants and conjugated them to MMAF to study the effect of isotype (IgG1, IgG2, and IgG4) and Fc receptor binding on antibody-drug conjugate properties. All IgG variants bound CD70⁺ 786-O cells with an apparent affinity of 1 nmol/L, and drug conjugation did not impair antigen binding. The parent anti-CD70 IgG1 bound to human FcRI and FcRIIIA V158 and mouse FcRIV and this binding was not impaired by drug conjugation. In contrast, binding to these Fc receptors was greatly reduced or abolished in the variant, IgG1v1, containing the previously described mutations, E233P:L234V:L235A. All conjugates had potent cytotoxic activity against six different antigen-positive cancer cell lines in vitro with IC₅₀ values of 30 to 540 pmol/L. The IgGv1 conjugate with MMAF displayed improved antitumor activity compared with other conjugates in 786-O and UMRC3 models of renal cell cancer and in the DBTRG05-MG glioblastoma model. All conjugates were tolerated to 40 mg/kg in mice. Thus, the IgG1v1 MMAF conjugate has an increased therapeutic index compared with the parent IgG1 conjugate. The improved antitumor activity of the IgG1v1 auristatin conjugates may relate to increased exposure as suggested by pharmacokinetic analysis. The strategy used here for enhancing the therapeutic index of antibody-drug conjugates is independent of the antigen-binding variable domains and potentially applicable to other antibodies. [Mol Cancer Ther 2008;7(9):2913–23]

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Note: Current address for C.F. McDonagh: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, MA 02139.

Current address for P.J. Carter: VLST, Inc., 307 Westlake Avenue North, Suite 300, Seattle, WA 98109.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/26/08; revised 5/19/08; accepted 6/20/08.