title: DCDT2980S, an anti-CD22-monomethyl auristatin E antibody-drug conjugate, is a potential treatment for non-Hodgkin lymphoma.
abstract: Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL.
authors.affiliation: Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Li
authors.forename: Kirsten Achilles
authors.initials: KA
authors.lastname: Poon
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.forename: Randall
authors.initials: R
authors.lastname: Dere
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Go
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lau
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.forename: Kristi
authors.initials: K
authors.lastname: Elkins
authors.forename: Dimitry
authors.initials: D
authors.lastname: Danilenko
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Pamela
authors.initials: P
authors.lastname: Chan
authors.forename: Josefa
authors.initials: J
authors.lastname: Chuh
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shi
authors.forename: Denise
authors.initials: D
authors.lastname: Nazzal
authors.forename: Franklin
authors.initials: F
authors.lastname: Fuh
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McBride
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Ruth
authors.initials: R
authors.lastname: de Tute
authors.forename: Andy
authors.initials: A
authors.lastname: Rawstron
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Jack
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: David
authors.initials: D
authors.lastname: Dornan
authors.forename: Marna
authors.initials: M
authors.lastname: Williams
authors.forename: William
authors.initials: W
authors.lastname: Ho
authors.forename: Allen
authors.initials: A
authors.lastname: Ebens
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008252:Macaca fascicularis; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009842:Oligopeptides / Q000494:pharmacology*; D011897:Random Allocation; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D051918:Sialic Acid Binding Ig-like Lectin 2; C000603979:pinatuzumab vedotin; C495575:monomethyl auristatin E