title: Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma.
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.
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA 94080, USA. polson@gene.com
authors.forename: A G
authors.initials: AG
authors.lastname: Polson
authors.forename: M
authors.initials: M
authors.lastname: Williams
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authors.initials: AM
authors.lastname: Gray
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authors.lastname: Fuji
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authors.initials: KA
authors.lastname: Poon
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authors.lastname: McBride
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authors.lastname: Raab
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authors.lastname: Januario
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authors.lastname: Go
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authors.lastname: Lau
authors.forename: S-F
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authors.lastname: Yu
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authors.lastname: Du
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authors.lastname: Fuh
authors.forename: C
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authors.lastname: Tan
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: W-C
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authors.lastname: Liang
authors.forename: S
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authors.lastname: Prabhu
authors.forename: J-P
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authors.lastname: Stephan
authors.forename: J-A
authors.initials: JA
authors.lastname: Hongo
authors.forename: R C
authors.initials: RC
authors.lastname: Dere
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authors.lastname: Deng
authors.forename: M
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authors.lastname: Cullen
authors.forename: R
authors.initials: R
authors.lastname: de Tute
authors.forename: F
authors.initials: F
authors.lastname: Bennett
authors.forename: A
authors.initials: A
authors.lastname: Rawstron
authors.forename: A
authors.initials: A
authors.lastname: Jack
authors.forename: A
authors.initials: A
authors.lastname: Ebens
mesh_terms: D000818:Animals; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy*; D008252:Macaca fascicularis; D009368:Neoplasm Transplantation; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*
chemical_list: D018796:Immunoconjugates; D051918:Sialic Acid Binding Ig-like Lectin 2