Incorporation of rituximab, a chimeric mAb directed against CD20, has transformed therapy and improved patient outcome in patients with B-cell malignancies including non-Hodgkin lymphoma and chronic lymphocytic leukemia. In MM mAbs directed against CD19, CD20, CD38, CD40, CD56, CD138, fibroblast growth factor receptor 3 (FGFR3), interleukin-6 (IL-6), and insulin-like growth factor-1 receptor (IGF-1R), either alone or coupled to toxins, have been or are under evaluation as potential novel therapeutics.2 However, evaluation of mAbs both for efficacy and toxicity profile in preclinical studies can be difficult. Factors in the bone marrow milieu, such as binding of MM cells to bone marrow, cytokines such as transforming growth factor-β (TGF-β), and T-regulatory cells may attenuate response. Moreover, although most investigators use subcutaneous xenograft models or SCID-hu models (tumor cells injected into human bone chips implanted into SCID mice)3 to assess potential utility of novel mAb therapies, the most important limitation is lack of cross-reactivity of the target antigen on human and murine MM and normal tissues. This drawback limits the ability of available models to reflect mechanisms both of tumor cytotoxity and toxicity to normal tissues, precluding the definition of a therapeutic index or window. For example, anti-CD138 immunotoxins are active against human MM cells in the presence of soluble CD138 in vitro, reflecting the shedding of soluble CD138 which occurs in patient serum, but the lack of cross-reactivity of human with murine CD138 makes it impossible to determine toxicity on normal tissues in preclinical murine models.4 As a consequence, mAbs may go forward clinically without preclinical toxicity data, often at very low doses and with gradual dose escalation studies.
In Brief
In the current study, Yi and colleagues elegantly show that treatment of human HLA-2 positive MM with anti-β2M mAb in an HLA-A2 transgenic mouse model allows for evaluation of its efficacy and toxicity in a setting reflecting the human MM patient, in whom HLA class I is expressed on normal tissues and β2M shed from MM cells is circulating in serum. As he and his coworkers have delineated mechanisms whereby anti-β2M mAb inhibits growth and survival as well as triggers apoptosis in vitro, this model is useful not only for predicting potential clinical application, but also for examining in vivo mechanisms of sensitivity versus resistance. Although, in the past, murine models have been criticized since they have not been predictive of either therapeutic efficacy or side effect profile, development of genetic models that faithfully reflect human setting, as the model of Yi, et al. does, may allow for more ready identification of those agents most likely to improve patient outcome.
References
Competing Interests
Dr. Anderson indicated no relevant conflicts of interest.