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Originally published as JCO Early Release 10.1200/JCO.2003.04.155 on July 1 2003 © 2003 American Society for Clinical Oncology
Bioweapons of Tumor Mass Destruction?MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom
You see we must take aim—aim by chemical variation! The marvellous effect of an antibody in the serum is due to the fact that in no case it has affinity for the body substances but flies straight onward without deviation, on the parasites. The antibodies are therefore MAGIC BULLETS which find the targets themselves. . . we must therefore concentrate all our powers and abilities on making the aim as accurate as we can contrive, so as to strike the parasites as hard and the body cells as lightly as possible. Paul Ehrlich, circa 1904
WE LIVE in momentous times. Recent advances in the diagnosis and therapy of lymphoma are, or threaten to be, as breathtaking and, it is hoped, more precise than the recent military campaign in Iraq. Genome-wide gene expression profiling allows the discrimination of biologically significant subsets of lymphoma, defines the key signaling pathways altered in each subset, and may allow the rational use and assessment of specific therapeutic approaches, such as inhibition of the NF- The availability of a panel of MAbs of various specificities for the treatment of the lymphomas and leukemias will have broad implications for the ways in which these diseases are managed. The clinical use of MAbs has to be firmly rooted in immunology and cancer cell biology because optimal use of each MAb will depend on precise mechanisms of action within defined tumor cell types (derived cell lines may not be suitable models, particularly for indolent B-cell diseases), biodistribution (MAb penetration into tumor masses is generally slow), pharmacokinetics (maintained low levels of MAb may be better under some conditions), and interactions with host effector mechanisms. Quantification of cell-surface antigen expression by the tumor should be carefully determined by flow cytometry because antigen density may be associated with clinical efficacy; detection of expression by immunohistochemistry alone may not be adequate. For CD22, for example, cytoplasmic expression may occur without significant cell surface membrane expression. In short, therapeutic MAbs need to be used according to immunologic rather than oncologic criteria—more may not necessarily be better. From clinical experience to date, it seems unlikely that any single MAb will be curative by itself. Major improvements are likely to arise via the simultaneous targeting of multiple different apoptotic pathways, or alternatively, by synergistic interactions with chemotherapy.4 However, any approach that uses multiple biologic agents will have significant resource implications. This problem is particularly acute in the United Kingdom, where the mechanisms to assess (and the government finances necessary to implement) expensive new agents in a timely fashion have been lacking. We are still coming to terms with the implications of possibly using rituximab in high-grade B-cell lymphoma (http://www.nice.org.uk/cat.asp?c=34,139). Rituximab is only the first of a potential armada of therapeutic MAbs and we are ill-prepared to meet the challenges of combination biotherapy. As an example of this process, the article by Leonard et al5 in this issue of the Journal of Clinical Oncology reports the first clinical phase I and II studies of a humanized CD22 MAb epratuzumab in 55 patients with relapsed, indolent B-cell lymphoma. The study is straightforward; four doses of 120 to 1,000 mg/m2 were administered at weekly intervals, with the aim of assessing safety, toxicity, and pharmacokinetics. At some higher doses (although notably not at the highest doses), nine patients with follicular B-cell lymphoma responded; three of these patients entered a complete remission. Maximal response rates of 43% were obtained at a dose of 360 mg/m2, with a median duration of response of 79 weeks. Patients with chronic lymphocytic leukemia did not appear to respond at the same rate, with 10 of 12 patients progressing between doses. Overall, responders had lower tumor burdens and had undergone fewer prior therapies than had nonresponders. Results of a larger series, including patients with diffuse large B-cell lymphoma, and preliminary data on the efficacy of the combination of epratuzumab and rituximab have been reported in abstract form at several meetings.5 These data are of considerable interest because they closely parallel and are possibly even better than those obtained with rituximab at the comparable stage of clinical development. Should epratuzumab therefore be used in the same, almost universal (indiscriminate) fashion, in all cell surface CD22+ B-cell malignancies?6 If not, what criteria should be used for the clinical development of this and subsequent MAbs? More generally, how can we identify molecules on the cell surface and, specifically, those epitopes that will be suitable for targeted therapy? Is there anything special about CD20 and CD22 MAbs, or will all MAbs to similar B-cell–specific molecules have comparable roles in therapy? There are no clear answers to these questions. Identification of the best therapeutic targets will depend on understanding the molecular functions of the target antigens and their associated signal transduction pathways. Some clues, however, may be derived by revisiting some of the early work done with murine MAbs in human hematologic malignancies.7 Results with these reagents were generally disappointing and not necessarily a result of the development of neutralizing antiglobulin responses. One of the major limitations was found to be antigenic modulation; that is, the internalization of a cell surface molecule after MAb-mediated cross-linking. This process can be extremely rapid and can effectively render a cell antigen negative and thus refractory to the effects of MAb. Neither CD20 nor CD52 (the target of alemtuzumab) modulate significantly in vivo, a feature considered to contribute significantly to the therapeutic efficacy of both MAbs. In contrast, CD22 does modulate in the presence of bivalent MAb. At first view, this would appear to make the molecule a poor target for therapy, at least via the activation of natural effector mechanisms such as antibody-dependent cell-mediated cytotoxicity and complement activation. Nevertheless, antibody-mediated cross-linking of CD22 on Burkitt’s lymphoma cell lines was capable of inducing apoptosis directly in vitro, which indicates that maintained CD22 signaling is somehow necessary for tumor cell survival. Interestingly, cross-linking of the B-cell receptor for antigen seemed to be synergistic with CD22 ligation.8 In addition, the efficacy of CD22 ligation may vary substantially according to the cell type. Thus, in murine B-cell lines, CD22 mediates a negative signal in immunoglobulin M (IgM)/IgD-expressing cells but a positive signal in IgG-expressing cells.9 These data may indicate a simple means of prospectively identifying patients likely to respond to epratuzumab. Antigenic modulation may be overcome by the use of monovalent antibodies. In this regard, a single-chain Fv CD22 antibody fragment linked to the Pseudomonas exotoxin subunit has shown considerable clinical activity in patients with relapsed hairy cell leukemia, inducing remission in 11 of 16 cladribine-resistant patients.10 In the light of the results reported here with epratuzumab, it is not clear how much of the activity of this reagent was due to the toxin moiety and how much was due to the targeting of CD22. Furthermore, the ability of CD22 to internalize in the presence of bivalent MAb makes this antigen a suitable target for approaches using radioimmunotherapy with alpha-emitting radioisotopes.11,12 Alternatively, naked CD22 molecules may themselves synergize with other radiolabeled MAbs.13 Whether small-molecule CD22-specific inhibitory molecules will have a role in tumor therapy remains unknown.14 Historically, combination chemotherapy has proceeded on an empirical basis. The same criteria have been applied to the clinical development of the CD20 MAb, rituximab, but are inadequate and indeed inappropriate for MAb therapy. The prospects for targeted therapy of lymphoid malignancies are unprecedented (see, for example, http://www.genmab.com/view_news.asp?filID=121), and the possible combinations are almost limitless. Rational (and cost effective) implementation will require new standards in both clinical diagnosis and monitoring. REFERENCES 1. Shaffer AL, Rosenwald A, Staudt LM: Lymphoid malignancies: The dark side of B-cell differentiation. Nat Rev Immunol 2:920–932, 2002[CrossRef][Medline] 2. Boyd RS, Adam PJ, Patel S, et al: Proteomic analysis of the cell-surface membrane in chronic lymphocytic leukemia: Identification of two novel proteins, BCNP1 and MIG2B. Leukemia (in press) 3. Mason DY, Andre P, Bensussan A, et al: CD antigens 2001. Tissue Antigens 58:425–430, 2002 4. Marsden VS, Strasser A: Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu Rev Immunol 21:71–105, 2003[CrossRef][Medline]
5. Leonard JP, Coleman M, Ketas JC, et al: Phase I and II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol 21:3051–3059, 2003
6. Boye J, Elter T, Engert A: An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 14:520–535, 2003
7. J Ritz J, Schlossman SF: Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma. Blood 59:1–11, 1982
8. Tuscano JM, Riva A, Toscano SN, et al: CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade. Blood 94:1382–1392, 1999
9. Wakabayashi C, Adachi T, Wienands J, et al: A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 298:2392–2395, 2002
10. Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 345:241–247, 2001 11. McDevitt MR, Scheinberg DA: Ac-225 and her daughters: The many faces of Shiva. Cell Death Differ 9:593–594, 2002[CrossRef][Medline] 12. Payne G: Progress in immunoconjugate cancer therapeutics. Cancer Cell 3:207–212, 2003[CrossRef][Medline]
13. Tuscano JM, O’Donnell RT, Miers LA, et al: The anti-CD22 ligand blocking antibody, HB22.7, has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts. Blood 101:3641–3647, 2003
14. Kelm S, Gerlach J, Brossmer R, et al: The ligand-binding domain of CD22 is needed for inhibition of the B cell receptor signal, as demonstrated by a novel human CD22-specific inhibitor compound. J Exp Med 195:1207–1213, 2002
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B pathway.
