High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate.
CD19 and CD21 (CR2) are co-receptors found on B-cells and various B-cell lymphomas, including non-Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization-dependent antibody-drug conjugates [such as antibody-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, (N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine) (MCC-DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B-cell lines. Anti-CD21 antibodies were not sufficiently internalized even in the highest CD21-expressing Raji cells, resulting in lack of efficacy with anti-CD21-MCC-DM1 conjugates. Anti-CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21-expressing Raji, ARH77 and primary B-cells only very slowly internalized anti-CD19 antibodies, while CD21-negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin-coated vesicles followed by lysosomal delivery. Anti-CD19-MCC-DM1 caused greater cytotoxicity in the faster anti-CD19-internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti-CD19 uptake and decreased anti-CD19-MCC-DM1 efficacy, suggesting that CD21-negative tumours should respond better to such anti-CD19 conjugates. This may have possible clinical implications, as anti-CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B-cell lymphoma patients lack CD21 expression.
Ingle
Gladys S
GS
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Chan
Pamela
P
Elliott
J Michael
JM
Chang
Wesley S
WS
Koeppen
Hartmut
H
Stephan
Jean-Philippe
JP
Scales
Suzie J
SJ
D000912:Antibodies, Neoplasm / Q000276:immunology*; D018941:Antigens, CD19 / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D002966:Clathrin / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D017464:Receptors, Complement 3d / Q000378:metabolism*
D000912:Antibodies, Neoplasm; D018941:Antigens, CD19; D002966:Clathrin; D018796:Immunoconjugates; D017464:Receptors, Complement 3d