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Therapy

Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma

Leukemia volume 24, pages 1566–1573 (2010)Cite this article

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Abstract

Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.

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Acknowledgements

We thank, Katharine C Lai and Erin K Maloney (Immunogen) for conjugation support, Klara Totpal for cell line production, David Xie for PK support, Kathy Howell and the PDB FACS facility for assistance in characterization of the B-cell subset assay in cynomolgus monkeys, Kathleen McKeever for oversight of the cynomolgus monkey safety study, Vanitha Ramakrishnan for critical reading and comments on the paper, Caroline Looney for assistance with the paper, Imola Fodor for statistical support, Fiona Zhong, Bing Zheng and Kristi Elkins for technical support, Darshana Patel and Susan Spencer for project management support and Sheila Bheddah, Linda Hall and Shari Lau for IHC support.

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  1. A G Polson, M Williams, A M Gray and R N Fuji: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Research and Early Development, Genentech, 1 DNA Way, South San Francisco, CA, USA

    A G Polson, M Williams, A M Gray, R N Fuji, K A Poon, J McBride, H Raab, T Januario, M Go, J Lau, S-F Yu, C Du, F Fuh, C Tan, Y Wu, W-C Liang, S Prabhu, J-P Stephan, J-A Hongo, R C Dere, R Deng & A Ebens

  2. Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Leeds, UK

    M Cullen, R de Tute, F Bennett & A Rawstron

  3. Department of Haematology, St James's Institute of Oncology, Bexley Wing, Beckett St, Leeds, UK

    M Cullen, R de Tute, F Bennett, A Rawstron & A Jack

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  1. A G Polson
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  2. M Williams
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Correspondence to A G Polson.

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Competing interests

AG Polson, M Williams, AM Gray, RN Fuji, KA Poon, J McBride, H Raab, T Januario, M Go, J Lau, S-F Yu, C Du, F Fuh, C Tan, Y Wu, W-C Liang, S Prabhu, J-P Stephan, J-A Hongo, RC Dere, R Deng and A Ebens are employees of Genentech, a subsidiary of Hoffman-LaRoche. M Cullen, R de Tute, F Bennett and A Rawstron and Andrew Jack receive funding from Genentech, a subsidiary of Hoffman-LaRoche.

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Polson, A., Williams, M., Gray, A. et al. Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma. Leukemia 24, 1566–1573 (2010). https://doi.org/10.1038/leu.2010.141

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