IntroductionIn the past decade, monoclonal antibodies directed against B-cell antigens have proven beneficial for patients with B-lineage neoplasms. Approved immunotherapeutics include the anti-CD52 antibody alemtuzumab (Campath-1H), 1 2 anti-CD20 antibodies, rituximab (Rituxan) 2 and most recently ofatumumab (Arzerra), 3 and 2 anti-CD20 conjugates carrying radioactive isotopes, 90 Yibritumomab tiuxetan (Zevalin) 4 and 131 I-tositumomab (Bexxar). 5 In particular, when used as a single agent or in combination with chemotherapy, rituximab has shown efficacy and relative safety in many B-cell non-Hodgkin lymphomas (NHLs) and some B-cell leukemias. 2,6 However, some patients do not respond to rituximab, and many of those that do will relapse. 2 In addition, some B-cell tumors either lack CD20 expression or lose it during rituximab treatment. 7 Thus, antibodies targeting other B-cell antigens are warranted, and several are being explored, including those targeting CD40, a 45-to 50-kDa transmembrane glycoprotein belonging to the tumor necrosis factor receptor family.CD40 is broadly expressed on hematologic cells, including B cells and on several types of epithelial and endothelial cells. [8][9][10] The ligand of CD40, CD40L (CD154), is preferentially expressed on activated T cells but has also been found on other hematologic cell types. Signaling via the CD40 pathway plays a key role in defining cellular and humoral immune responses. 10 CD40 is overexpressed by the malignant counterparts to Blineage cells and is found on most mature B-cell malignancies, including NHL, Hodgkin disease, and chronic lymphocytic leukemia (CLL), and on some early acute lymphocytic leukemias (ALL) 8,11,12 ; it is also expressed on multiple myeloma (MM) cells. 13 Many solid tumors express CD40, including melanoma and carcinomas of the kidney, bladder, lung, pancreas, colon, prostate, ovary, breast, head, and neck. 14 CD40 agonists have been shown to trigger immune responses against various tumors 15,16 and to inhibit the growth of different neoplastic cells, both in vitro and in vivo. 17,18 Broad stimulation of the immune system and expression on a wide range of malignancies make CD40 an attractive target for antibody-based immunotherapy. Over the past 2 decades, several CD40-specific antibodies have been tested against B-lineage malignancies in vitro and in animal models, yielding various degrees of success. [19][20][21][22][23] Recently, 2 humanized antibodies have emerged for further development: a mild CD40 agonist, 20,24,25 and a CD40 antagonist, HCD122 (CHIR-12.12). 21,23 These agents were evaluated in phase 1 and 2 trials in patients with relapsed MM, NHL, and CLL. Thus far, they have demonstrated a favorable safety profile and have shown some antitumor activity in NHL and MM. [26][27][28] In addition, a strongly agonistic anti-CD40 antibody, CP-870,893, evaluated in phase 1 trials in patients with melanoma and other solid tumors, was found to be well tolerated and to have antitumor activity. 29 Therefore, preclinical and early clinic...