title: Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas.
abstract: Despite major advances in the treatment of non-Hodgkin lymphoma (NHL), including the use of chemotherapeutic agents and the anti-CD20 antibody rituximab, the majority of patients eventually relapse, and salvage treatments with non-cross-resistant compounds are needed to further improve patient survival. Here, we evaluated the antitumor effects of the microtubule destabilizing agent monomethyl auristatin E (MMAE) conjugated to the humanized anti-CD19 antibody hBU12 via a protease-sensitive valine-citrulline (vc) dipeptide linker. hBU12-vcMMAE induced potent tumor cell killing against rituximab-sensitive and -resistant NHL cell lines. CD19 can form heterodimers with CD21, and high levels of CD21 were reported to interfere negatively with the activity of CD19-targeted therapeutics. However, we observed comparable internalization, intracellular trafficking, and drug release in CD21(low) and CD21(high), rituximab-sensitive and -refractory lymphomas treated with hBU12-vcMMAE. Furthermore, high rates of durable regressions in mice implanted with these tumors were observed, suggesting that both rituximab resistance and CD21 expression levels do not impact on the activity of hBU12-vcMMAE. Combined, our data suggest that hBU12-vcMMAE may represent a promising addition to the treatment options for rituximab refractory NHL and other hematologic malignancies, including acute lymphoblastic leukemia.
authors.affiliation: Department of Preclinical Therapeutics, Seattle Genetics, Bothell, WA 98021, USA. hgerber@seagen.com
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
authors.forename: May
authors.initials: M
authors.lastname: Kung-Sutherland
authors.forename: Ivan
authors.initials: I
authors.lastname: Stone
authors.forename: Carol
authors.initials: C
authors.lastname: Morris-Tilden
authors.forename: Jamie
authors.initials: J
authors.lastname: Miyamoto
authors.forename: Renee
authors.initials: R
authors.lastname: McCormick
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Alley
authors.forename: Nicole
authors.initials: N
authors.lastname: Okeley
authors.forename: Brad
authors.initials: B
authors.lastname: Hayes
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: McDonagh
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Carter
authors.forename: Dennis
authors.initials: D
authors.lastname: Benjamin
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D002956:Citrulline / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004151:Dipeptides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D018628:Gene Dosage; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000378:metabolism / Q000627:therapeutic use*; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab; D014633:Valine / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D004151:Dipeptides; D018796:Immunoconjugates; D009842:Oligopeptides; D017464:Receptors, Complement 3d; D002956:Citrulline; D000069283:Rituximab; D014633:Valine; C495575:monomethyl auristatin E