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Clinical Cancer Research Vol. 9, 3991S-3994S, September 1, 2003
© 2003 American Association for Cancer Research

Session V: CLINICAL STUDIES: HEMATOLOGICAL TUMORS

Epratuzumab

Targeting B-Cell Malignancies through CD221

Morton Coleman2, David M. Goldenberg, Abby B. Siegel, Jamie C. Ketas, Michelle Ashe, Jennifer M. Fiore and John P. Leonard

Center for Lymphoma and Myeloma, Division of Hematology/Oncology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York 10021 [M. C.]; Garden State Cancer Center, Belleville, New Jersey 07109; and Immunomedics, Inc., Morris Plains, New Jersey 07950


   ABSTRACT
Top
 ABSTRACT
Introduction
 CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 
The development of effective B cell-directed monoclonal antibody therapies has dramatically altered the management of patients with B-cell non-Hodgkin’s lymphoma. Anti-CD20 murine and chimeric antibodies have been characterized by manageable toxicity profiles and appear to have mechanisms which may be distinct from and complementary to those of chemotherapy. There is considerable rationale for treatment strategies which target other B-cell antigens, including CD22. This molecule is commonly expressed in non-Hodgkin’s lymphoma and may mediate important functions in B-cell biology. Laboratory and initial clinical studies suggest that epratuzumab, a humanized anti-CD22 monoclonal antibody, may have antilymphoma activity in both unlabeled and radiolabeled forms. Efforts are underway to establish the utility of epratuzumab as a treatment for B-cell malignancies, through single agent and combination regimens, to define the optimal settings for its clinical application.


   Introduction
Top
 ABSTRACT
 Introduction
CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 
NHL3 is comprised of a heterogeneous group of malignancies which all represent neoplasms of lymphocytes. Although numerous NHL subtypes have been recognized, the most commonly observed entities are FL and LCL.

Chemotherapy, along with radiotherapy, has served as the mainstay of treatment for decades. The first significant departure from exclusive reliance on these therapeutics came from the FDA approval and introduction of rituximab, an unlabeled ("naked" or "cold") chimeric monoclonal antibody directed toward the CD20 antigen, which is anchored to the surface of most B-cell lymphoma cells. The demonstration that rituximab could produce >=60% objective responses in low-grade NHL patients (depending on histology and previous therapy) with minimal toxicity has significantly impacted clinical practice and sparked enormous enthusiasm for this new modality of therapy (1, 2, 3, 4, 5, 6, 7) . Subsequent studies have suggested that rituximab may be easily combined either sequentially or concurrently with chemotherapy, with acceptable side effects and potentially improved efficacy (8, 9, 10, 11) .

Although rituximab has proven especially beneficial to FL patients, a substantial proportion of patients do not respond, and almost every responding patient ultimately relapses, usually at a median of 9–12 months. Nevertheless, rituximab, representing proof of principle for the clinical application of antibodies in NHL, has prompted the search for new antibodies directed to other B cell lineage-specific antigen targets which may exhibit different patterns of tumor expression or may be associated with biological properties distinct from those of CD20.


   CD22 as a Target for Immunotherapy
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 
A variety of lymphocyte antigens is currently under evaluation as targets for immunotherapy. These include CD22, CD52, HLA-DR, CD80, and CD30. All have preliminarily exhibited encouraging results in preclinical or clinical studies (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) . It has been hypothesized that antibodies against other lymphoma antigens may have antilymphoma effects that could overcome rituximab resistance or augment the activity of rituximab.

The CD22 antigen is a Mr 135,000 B-lymphocyte-restricted transmembrane sialoglycoprotein of the immunoglobulin superfamily. The predominant CD22 isoform contains seven extracellular domains (29 , 30) . CD22 is initially present in the cytoplasm of developing B cells but is later expressed on the surface during B-cell maturation once IgD expression occurs (31) . Most circulating IgM+IgD+ cells express CD22. CD22 is strongly expressed in follicular (primary and secondary, B-cell zones), mantle, and marginal zone B cells but is weakly present in germinal (activated or differentiating) B cells. In B-cell malignancies, CD22 has been observed in >=60–80% of samples evaluated (32) . However, limited data are available with regard to expression of different CD22 isoforms in various NHL subtypes. When bound by ligand or antibody, CD22 is rapidly internalized within hours; internalization is "terminal," and re-expression is slow (days) (33 , 34) . The function of CD22 has not been entirely clarified, but reports have implicated a number of biological activities, including cellular adhesion and homing, as well as regulation of the B-cell activation (31 , 35, 36, 37, 38) . Notably, CD22-deficient mice have mature B cells which may be more susceptible to apoptotic signals, have a shorter cellular life span, and are reduced in number in the bone marrow (39) .


   Potential Advantages of a Humanized Antibody Structure
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
 Potential Advantages of a...
Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 
Most monoclonal antibodies had been initially generated in a murine form and sometime later were modified to either chimeric (part murine and part human) or humanized forms. Favorable characteristics of humanized antibodies may include a more extended half-life, which potentially allows for extended dosing intervals, and reduced immunogenicity, which confers value for multiple dose strategies. These qualities have potentially important relevance to dosing regimens and pharmacokinetics that may affect the therapeutic response and toxicity. Antibody structure may also impact the capability of an individual antibody to mediate effector cell killing through binding to Fc receptors (40) . Various investigators are actively developing approaches which optimize antibody structure to improve engagement of the immune system to potentially improve antitumor effects. Other approaches include the addition of radioisotopes or toxins to antibodies to deliver additional modalities, which may also induce cell death (17 , 19 , 41, 42, 43, 44, 45, 46, 47) .


   Epratuzumab (Humanized LL2)
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 
Epratuzumab is a humanized IgG1 monoclonal antibody directed against the CD22 antigen. Its parent murine antibody (LL2) has a broad range of reactivity against various B-cell lymphoma subtypes as demonstrated by immunohistochemistry (48) , with little binding to normal tissue except for spleen. The antibody is rapidly internalized after attachment to CD22 (34) . The murine LL2 antibody was subsequently re-engineered into the humanized (hLL2) epratuzumab (16) . A number of different studies has been or are being conducted with both murine and humanized radiolabeled (Iodine-131 and Yttrium-90) forms of LL2, as well as with the unlabeled humanized form (epratuzumab; Immunomedics, Morris Plains, NJ, and Amgen, Thousand Oaks, CA). Laboratory investigations of putative mechanisms of action of epratuzumab as antilymphoma therapy are also underway. Antibody-dependent cellular cytotoxicity, as well as other pathways, may potentially be involved, similarly to those implicated in the activity of other therapeutic antibodies (49, 50, 51, 52) .


   Clinical Studies of Unlabeled Epratuzumab (hLL2)
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
Conclusion and Future Directions
 REFERENCES
 
Although initial studies of epratuzumab focused on evaluation of radiolabeled constructs, several characteristics of unlabeled antibodies justify a parallel development strategy. Unlike radiolabeled agents, anti-B cell unlabeled antibodies are generally not associated with myelosuppression, facilitating treatment of patients with pre-existing cytopenias and extensive bone marrow involvement with tumor. Additionally, unlabeled antibodies are easier to combine with chemotherapy and other agents because of nonoverlapping toxicities. These attributes, in addition to the unique properties of the target CD22 antigen, all provided an impetus for the study of unlabeled epratuzumab in B-cell malignancies.

At the Center for Lymphoma and Myeloma at the Weill Medical College of Cornell University and the New York Presbyterian Hospital, we have explored the use of epratuzumab in patients with a variety of relapsed and refractory B-cell malignancies (53) . An initial dose escalation trial used epratuzumab at i.v. doses from 120 to <=1000 mg/m2/week for four treatments, given generally over 30–60 min. Premedication with acetaminophen and diphenhydramine was provided to minimize the potential for infusion reactions. Treated subjects were heavily pretreated, with half having received four or more previous treatment regimens. Other adverse prognostic features were commonly present, including increased lactate dehydrogenase and tumor masses of >=5 cm. Epratuzumab was very well tolerated across all dose levels examined, even when infused over <=1 h. Infusion toxicities have been primarily grade 1 and manageable with usual supportive measures. Some patients exhibited transient B-cell depletion, but no other consistent laboratory abnormalities have been observed. No dose-limiting toxicity was observed, although for logistical reasons, escalation beyond 1000 mg/m2/week was not performed. Among initial groups of FL, patients treated across all dose levels (n = 40), three complete and six partial responses, were preliminarily observed. Among the first group of LCL patients receiving epratuzumab, five objective responses were noted, including three complete responses. Overall responses appear to be more frequent around the 360 and 480 mg/m2 dose levels (Fig. 1)Citation . Some of the responses have extended as long as several years. The tolerability and clinical activity in FL and LCL have suggested that further evaluation of this agent in NHL is warranted.



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  		Fig. 1. Objective response rates by dose for evaluable patients with follicular NHL in Phase I/II study of epratuzumab in indolent NHL. The 95% confidence intervals were 11–40%, 18–71%, and 6–61% for the rates for overall, the 360 mg/m2, and the 480 mg/m2 groups, respectively. Reproduced from Leonard et al. (54) with permission from the authors and publisher.

 
This preliminary evidence of antilymphoma activity led our group to study the concomitant use of epratuzumab and rituximab, to our knowledge the first study of combination antibody therapy in lymphoma. Because the mechanisms of action of the two agents may be different, and the targets are distinct, it is possible that the addition of epratuzumab may augment the activity of an anti-CD20-based regimen. Of course, one could theoretically postulate reduced efficacy of a combination, through a deleterious effect, although with disparate targets, a competition effect would be less likely. Additionally, the toxicity profile of a combination immunotherapy strategy may be potentially more favorable relative than that of chemotherapy or radioimmunotherapy. Preliminary evaluation of the combination of epratuzumab and rituximab in B-cell NHL has yielded encouraging findings (54) . Patients have received 360 mg/m2 epratuzumab followed by 375 mg/m2 rituximab weekly for four doses. Subjects have predominantly fallen into the FL and LCL categories, and early enrolling patients were rituximab naïve. Combination therapy was well tolerated with infusion-related toxicities National Cancer Institute grade I or II and comparable with those seen with antibody monotherapy. Objective responses have been demonstrated in the majority of patients (preliminarily 66% of follicular patients), and the quality of responses as reflected by complete responses and complete responses unconfirmed (preliminarily 60% in follicular patients) appear to be greater than expected with rituximab alone. Extended follow-up and additional accrual are necessary to validate our initial impressions, but these preliminary results suggest that this combination antibody regimen may be well tolerated and offers encouraging antilymphoma activity.

A number of other clinical trials with epratuzumab are either ongoing or expected, including studies of single agent epratuzumab in various B-cell lymphomas, multicenter evaluation of the epratuzumab and rituximab combination in FL and LCL, and studies of epratuzumab with chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, with rituximab as primary therapy for LCL.


   Conclusion and Future Directions
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
REFERENCES
 
Considerable challenges still remain to elucidate the biology and function of epratuzumab and in the determination of the optimal setting for its use in B-cell malignancies. The evolving clinical data suggest that, ultimately, epratuzumab may have a significant role among the array of therapies available for lymphoma patients and will hopefully contribute to an improved therapeutic outlook for them.

Initial findings appear to indicate that epratuzumab has clinical activity as well as acceptable toxicity in FL and LCL. The unique characteristics of the CD22 target, and the properties of the humanized antibody structure, may contribute to these encouraging effects. Further evaluation of the in vitro and clinical characteristics of this treatment approach are under way, including more extended follow-up and additional patients among a variety of clinical studies. Although single agent activity of epratuzumab may be useful, a combination antibody therapy approach is particularly appealing, especially if toxicity is no greater, if the number and/or quality of responses ultimately prove to be better. While over the last several decades investigators have focused on combination chemotherapy strategies for lymphoma, we now have the option to potentially avoid the use of chemotherapy (and its associated toxicities) in certain clinical situations through use of combinations of biological agents, which specifically target malignant cells.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. Supported in part by a K23 award (to J. P. L) from the NIH (RR16814-02) and a pilot grant from the Cornell Center for Aging Research and Clinical Care (to J. P. L.). Back

2 To whom requests for reprints should be addressed, at Weill Medical College of Cornell University, 407 East 70th Street, New York, NY 10021. E-mail: mortoncolemanmd{at}aol.com Back

3 The abbreviations used are: NHL, non-Hodgkin’s lymphoma; FL, follicular lymphoma; LCL, large B-cell lymphoma. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 CD22 as a Target...
 Potential Advantages of a...
 Epratuzumab (Humanized LL2)
 Clinical Studies of Unlabeled...
 Conclusion and Future Directions
 REFERENCES
 

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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online