The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells

Abstract

B-cell chronic lymphocytic leukemia (B-CLL IntroductionChronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and is characterized by progressive accumulation of malignant B cells in the blood, bone marrow, and lymphoid organs. CLL has been considered a prime example of a malignancy involving defects in the regulation of cell death; the slow accumulation of B-cell CLL (B-CLL) cells is presumably the result of a low proliferative index coupled with an intrinsic defect in apoptosis. However, recent clinical data from B-CLL patients given deuterated water have shown that there is a considerably higher turnover of CLL cells than previously recognized, 1 and that rates of B-CLL cell proliferation, as well as cell death, can vary widely among the lymphatic and extralymphatic compartments. Observations from other studies suggest that there are 2 types of malignant cells: quiescent and apoptosis-resistant cells in the blood, and actively dividing cells found in lymphatic aggregates in the lymph nodes and bone marrow. 2 B-CLL cells in peripheral blood are arrested in the G0/G1 phase of the cell cycle 3 and express high levels of the cell-cycle inhibitor p27. 4 In contrast, Survivinand Ki67-positive B-CLL cells, 5 and those with low expression of p27, 6 have been identified in proliferation centers of the lymph nodes and bone marrow. Thus, the goal of developing therapeutics to treat and cure CLL is to disrupt the pathologic conditions that promote malignant cell growth while accelerating tumor cell death and clearance.Until recently, treatment of progressive CLL, with steroids and alkylating agents, was largely palliative, with no impact on the natural history of the disease. 7 Introduction of purine analogs as single-agent therapies (fludarabine [F]) 8 and in combination with alkylators (fludarabine/cyclophosphamide [FC]) 9 has improved clinical responses and complete remission rates. Purine analogues have a high specificity for lymphoid cells and can induce death in both proliferating and resting cells. As a result, these agents are as effective as single agents for treating bulky CLL disease, and substantially reduce tumor burden with little extramedullary toxicity. Severe myelosuppression and immunosuppression are, however, associated with this class of drugs, and despite improvements in clinical responses, an increase in median survival time has not been demonstrated. Addition of the monoclonal antibody rituximab Rituxan; Genentech [South San Francisco, CA] and IDEC Pharmaceuticals [San Diego, CA]) to FC regimens has resulted in significantly higher overall response rates (ORRs), complete responses (CRs), molecular remissions, and importantly, longer median overall survival. 10-12 Grades 3 to 4 myelosuppression, infection, and viral reactivation remain major morbidities.Monoclonal antibodies have demonstrated activity in CLL as single agents, fueling interest in targeted therapeutic agents that engage the immune effector system to kill tumor cells. Alemtuzumab (CamPath; Millenniu...

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

“…27 Not all CLL clones respond to CD40 stimulation in vitro, indicating a clonal functional heterogeneity. 1,17,18 This is relevant considering that CD40 has attracted great interest as a potential therapeutic target in CLL, 28,29 and in ongoing clinical trials either activation of CD40 by genetically modified leukemic cells expressing CD40L gene 30 or CD40 inhibition with anti-CD40 antagonist antibody 31 are used in different therapeutic strategies.…”

Interaction with FcγRIIB Is Critical for the Agonistic Activity of Anti-CD40 Monoclonal Antibody

“…In our studies of therapeutic mAb, their potency is unprecedented, clearing bulk tumors from mice with established disease and providing immunity to rechallenge (20,24). To date, four anti-CD40 mAb 893 (31), , HCD122 (26,33)], and Chi LOB7-4 (34) have been investigated in phase I/II trials. These reagents show diverse activities ranging from antagonist (HCD122) to strong agonist (CP-870,893) (26).…”

BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma

“…33 Extensive in vitro studies identified many pathways and factors that enhance CLL cell survival and promote limited proliferation, including TLRs, cytokines, chemokines, CD40, B-cellactivating factor of tumor necrosis factor family (BAFF), integrins, and components of the extracellular matrix. 22,25,31,[34][35][36][37][38] Many of these extrinsic factors signal through SYK, PI3K␦, and BTK and activate similar intracellular pathways, most prominently the PI3K/ AKT/mTOR, NF-B, and MAPK pathways. It is therefore difficult to estimate to what degree any single factor or pathway may be necessary or sufficient for CLL pathogenesis.…”