The development of novel treatments such as those based on human monoclonal antibodies (mAb) are currently being evaluated in preclinical and early clinical studies in cancers. There is convincing evidence supporting a key role for antibody-dependent cell-mediated cytotoxicity (ADCC) in the clinical response of several therapeutic monoclonal antibodies. In myeloma, CD38 and CD138, both highly expressed by all myeloma cells, represent the best targets for ADCC and humanized Abs are currently in development for both antigens. The aim of the present study was to assess the CD38 and CD138-ADCC sensitivity of a large panel of human myeloma cell lines (HMCLs) representative of the disease heterogeneity.
To reproductively assess ADCC, we used mouse FcgRIII expressing human T lymphocytes as cytotoxic effector cells. We measured ADCC sensitivity of 20 HMCLs with two mouse IgG1 anti-CD38 (clones T16 and HIT2), with two mouse IgG1 anti-CD138 (clones BB4 and MI15) and with a mouse IgG2a anti-HLA class-I (clone W6.32) by a standard 51Cr release assays performed at an effector to target ratio of 10:1.
Unexpectedly, despite high level of CD38, only 3 cells lines among 20 were sensitive to anti-CD38/ADCC. No correlation was observed between anti-CD38/ADCC sensibility and the CD38 expression level. No correlation was observed too between sensitivity and representative molecular heterogeneity of HMCLs. The absence anti-CD38/ADCC was not due to intrinsic resistance lysis through ADCC since these cell lines were lysed when using an anti-HLA class-I mAb (or anti-CD20 mAbs for one CD20+ HMCL). Furthermore, absence of ADCC was not due to antibody-induced antigenic modulation. Surprisingly too, none HMCL was lysed by anti-CD138 mAbs despite high expression of CD138. Moreover, primary myeloma cells purified from peripheral blood of a patient were also resistant to both anti-CD38 and anti-CD138 mAbs.
These results show that ADCC activity mediated by a particular monoclonal antibody varies according to the target cell and independently of the antigen expression level, suggesting that the antigen “environment” might affect the interactions between antibody, Fc receptor and effector cells. Further studies will be required to determine the CD38 and CD138 “environment” factors on myeloma cell that can influence ADCC.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.