An ongoing phase I study is evaluating the safety and highest tolerated dose of MDX-1411 in patients with relapsed/refractory CLL and mantle-cell lymphoma. Galiximab. B-cell malignancies. INTRODUCTION Monoclonal antibodies (mAbs) have dramatically changed the management of patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Since the approval of the human-murine immunoglobulin (Ig) G1 anti-CD20 mAb rituximab, multiple studies have evaluated the activity of this and other mAbs, either alone or in combination with chemotherapeutic backbones, for the treatment of B-cell malignancies. On binding to CD20, rituximab induces antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis of CLL cells1C3 and sensitizes malignant B cells to chemotherapy.4 The addition of rituximab to chemotherapeutic regimens (ie, cyclophosphamide, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; fludarabine, mitoxantrone, and dexamethasone) produced a remarkable increase in overall response rates (ORR) and complete remission (CR) rates, as well as delay of time to progression (TTP).5 The addition of rituximab to CHOP chemotherapy (R-CHOP) improved CR rates and prolonged 5-year overall survival Naphthoquine phosphate (OS) rates by more than 10% in patients with diffuse large B-cell lymphoma (DLBCL).6C9 Although single-agent rituximab renders modest results in CLL,10C14 likely owing to the low CD20 expression on CLL cells,15 combination chemoimmunotherapy with rituximab, fludarabine, and cyclophosphamide (FCR) results in higher ORR (95% 88%), CR rates (52% 27%), and improved progression-free survival (PFS; 76.6% 62.3%) compared Naphthoquine phosphate with fludarabine and cyclophosphamide therapy.16 Although targeting surface antigens with mAbs provides an efficacious option for the management of B-cell malignancies, it is clear that current immune approaches have limitations and that clinical outcomes can still be significantly improved. ARE NOVEL AGENTS REALLY NEEDED IN B-CELL NHL AND CLL? On re-treatment with a relapse therapy, most patients with B-cell malignancies may be considered for allogeneic transplantation. However, suitable donors are not always available, and transplantation-related complications remain a concern, which underscores the importance of developing novel chemoimmunotherapeutic regimens to improve CR rates, as well as TTP and OS in previously untreated patients. Approximately 50% of patients with relapsed/refractory CD20+ follicular lymphoma (FL) fail to respond to initial rituximab therapy,17 and nearly 60% of those with an initial response eventually become rituximab resistant.18 In addition, some patients exposed to rituximab-based chemoimmunotherapy fail to respond or experience relapse within 6 months, also suggesting resistance to therapy. Furthermore, disorders such as CLL/small-cell lymphoma (SLL) are less responsive than other NHLs to standard-dose single-agent rituximab. The success of rituximab in the treatment of B-cell malignancies, but also its recognized limitations, has spurred investigational efforts to engineer mAbs that target different surface antigens expressed on malignant B cells. One example of the latter is the development of alemtuzumab, an anti-CD52 mAb, for the treatment of CLL. In the international phase III randomized CAM307 trial, alemtuzumab rendered higher ORRs (83% 55%), CR rates (22% 2%), minimal residual disease (MRD) eradication (31% 0%), and longer time to alternative Naphthoquine phosphate treatment (23.3 14.7 months) and PFS compared with chlorambucil in patients with previously untreated CLL.19 Several mechanisms of resistance may prevent some patients from responding to therapy. For instance, the presence of membrane-complement regulatory proteins such as CD55 and/or CD59 on CLL cells may potentially impair complement activation and reduce the formation of the membrane attack complex, thus protecting the tumor cell from antibody-mediated CDC.1,2,15 However, a clear correlation between the expression of CD55 and CD59 with resistance to rituximab-induced cell killing and Rabbit Polyclonal to ARHGEF11 clinical response has not been consistently established.1 In addition, pharmacokinetic factors, downregulation or modification of target surface antigens, or limited proapoptotic activity may also play a role in the resistance to currently available mAbs.20C22 Therefore, novel immunotherapeutics with different mechanism of action are required to improve the current therapies for B-cell Naphthoquine phosphate malignancies. INVESTIGATIONAL mAbs IN CLINICAL DEVELOPMENT The success of rituximab therapy has validated CD20 as a therapeutic target in.