Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas.
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.
Gerber
Hans-Peter
HP
Department of Preclinical Therapeutics, Seattle Genetics, Bothell, WA 98021, USA. hgerber@seagen.com
Kung-Sutherland
May
M
Stone
Ivan
I
Morris-Tilden
Carol
C
Miyamoto
Jamie
J
McCormick
Renee
R
Alley
Stephen C
SC
Okeley
Nicole
N
Hayes
Brad
B
Hernandez-Ilizaliturri
Francisco J
FJ
McDonagh
Charlotte F
CF
Carter
Paul J
PJ
Benjamin
Dennis
D
Grewal
Iqbal S
IS
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
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