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High CD21 expression inhibits internalization of anti‐CD19 antibodies and cytotoxicity of an anti‐CD19‐drug conjugate
Author(s) -
Ingle Gladys S,
Chan Pamela,
Elliott J Michael,
Chang Wesley S,
Koeppen Hartmut,
Stephan JeanPhilippe,
Scales Suzie J
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06883.x
Subject(s) - internalization , cd19 , antibody , antibody drug conjugate , chemistry , cytotoxicity , microbiology and biotechnology , raji cell , cd22 , b cell , monoclonal antibody , cancer research , receptor , in vitro , biology , immunology , biochemistry
Summary 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, ( N 2′ ‐deacetyl‐ N 2′ ‐(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.