title: A Novel Anti-CD22 Anthracycline-Based Antibody-Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs.
abstract: OBJECTIVE
  We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance.
  
  
  METHODS
  Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.
  
  
  RESULTS
  We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.
  
  
  CONCLUSIONS
  These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates.
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Go
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Lau
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Spencer
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Soriano
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Nerviano Medical Sciences, Nerviano MI, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Flygare
authors.affiliation: Research and Early Development, Genentech Inc., South San Francisco, California. polson@gene.com.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C502356:3'-deamino-3'',4'-anhydro-(2''-methoxy-3''-oxy-4''-morpholinyl)doxorubicin; D062365:Aminobenzoates; D018943:Anthracyclines; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D051918:Sialic Acid Binding Ig-like Lectin 2; C543533:auristatin; D004317:Doxorubicin