Blood, 1 October 2007, Vol. 110, No. 7, pp. 2218.
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NEOPLASIA
Comment on Zhao et al, page 2569
Immunotherapy of B-cell malignancies: first MABs, now SMIPs
Richard R. Furman, and
John P. Leonard
WEILL CORNELL MEDICAL COLLEGE; NEW YORK PRESBYTERIAN HOSPITAL
Zhao and colleagues report on a novel small modular immunopharmaceutical (SMIP) directed against CD37 in chronic lymphocytic leukemia (CLL). This agent offers several potential design advantages, and demonstrates interesting preclinical activity through mechanisms of action different from standard therapies.
Since the approval of the chimeric anti-CD20 rituximab in 1995, the use of monoclonal antibodies has dramatically altered the treatment of hematologic malignancies. Subsequently, 2 radiolabeled anti-CD20 molecules, a chemotherapy-conjugated anti-CD33, and the anti-CD52 alemtuzumab have followed, with a host of others currently in preclinical and clinical studies. Over this time period, antibody-based therapeutics have evolved principally in 2 areas. First, attempts have been made to alter the nature of antibody structure. Such changes have been designed to enhance killing activity (through mechanisms such as antibody–dependent cellular cytotoxicity or complement activation), improve pharmacokinetics, or make the antibody "humanized" or fully human. The second area involves the use of novel targets. CD20 has been the most commonly exploited antigen because of its restriction to the B lineage, its membrane stability, and its widespread expression in lymphoid malignancies. Therapies directed toward other antigens with different structure, function, and expression patterns can provide alternative antitumor effects.
In this issue of Blood, Zhao and colleagues describe a new direction in the immunotherapy of lymphoid malignancies. They report on a novel anti-CD37 small modular immunopharmaceutical (SMIP), an attempt to both enhance antibody structure and to evaluate an underexplored target. Either aspect would individually represent an interesting strategy in this arena. The CD37-SMIP uses human immunoglobulin (Ig) variable region (light and heavy chain) linked to an IgG1 hinge region and 2 gamma heavy chain constant regions (CH2 and CH3). All components are human in sequence, and the entire molecule is a single-chain polypeptide—resulting in the binding and effector function of a monoclonal antibody but at one-third to one-half the size (see the figure). These design features may allow an SMIP to overcome 3 potential obstacles to effectiveness: (1) limited tissue penetration seen relating to large antibody size; (2) limited cellular effector functions in patients due to prior exposure to cytotoxics; and (3) short half-life of small polypeptides due to serum proteases and filtration at the glomerulus. The single chain and modular function of SMIPs also make subsequent adaptation to other targets and clinical production feasible.
Earlier work by others showed that CD37 is commonly expressed in CLL and other mature B-cell malignancies, though its precise function is unknown.1,2 The evaluation of this target in CLL is of particular interest, given the limited activity of rituximab in this setting, partly due to lower expression of CD20. Zhao and colleagues demonstrate that CD37-SMIP induces apoptosis of CLL cells at least equal to that of rituximab and alemtuzumab, and this activity requires crosslinking of CD37-SMIP in vitro and correlates with the level of CD37 expression. This apoptosis is mediated by different pathways from those seen with fludarabine, in that it is not inhibited by caspase inhibition, does not result in PARP cleavage,3 and is blocked by herbimycin, an inhibitor of tyrosine phosphorylation. Further experiments demonstrate greater antibody-dependent cellular cytotoxicity (ADCC) activity (which is mediated by NK cells) by CD37-SMIP than that observed with rituximab or alemtuzumab, with an absence of complement-dependent cytotoxicity noted.
Considerable challenges exist in the clinical development of novel immunotherapeutics in hematologic malignancies, particularly with respect to integration of new agents with standard approaches. Nonetheless, these preclinical data suggest that the nature of the target and pathways of activity for CD37-SMIP may allow it to overcome some of the limitations of alternative therapies. Whether SMIP molecules represent a major leap forward in immunotherapy remains to be seen, but we eagerly anticipate their further evaluation in patients.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Belov L, de la Vega O, dos Remedios CG, Mulligan SP, Christopherson RI. Immunophenotyping of leukemias using a cluster of differentiation antibody microarray. Cancer Res 2001; 61:4483–4489.[Abstract/Free Full Text]
- Zhao XB, Trupti J, Lapalombella R, et al. NK cells contribute significantly to the innate immune effector role of CD37-specific SMIP in CLL and NHL [abstract 135]. Blood 2006; 108:135.
- Lapalombella R, Zhao XB, Grosmaire L, Ledbetter JA, Muthusamy N, Byrd JC. CD37-SMIPTM drug induced caspase independent cellular cytotoxicity is associated with activation of phosphotyrosine-mediated signalling events in primary chronic lymphocytic leukemia (CLL) B cells [abstract 2097]. Blood 2006; 108:2097.
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Related Article in Blood Online:
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Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical
- Xiaobin Zhao, Rosa Lapalombella, Trupti Joshi, Carolyn Cheney, Aruna Gowda, Martha S. Hayden-Ledbetter, Peter R. Baum, Thomas S. Lin, David Jarjoura, Amy Lehman, Donna Kussewitt, Robert J. Lee, Michael A. Caligiuri, Susheela Tridandapani, Natarajan Muthusamy, and John C. Byrd
Blood 2007 110: 2569-2577.
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