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Harnessing the Fcm Receptor for Potent and Selective Cytotoxic Therapy of Chronic Lymphocytic Leukemia

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Harnessing the Fcm Receptor for Potent and Selective Cytotoxic Therapy of Chronic Lymphocytic Leukemia Published OnlineFirst October 24, 2014; DOI: 10.1158/0008-5472.CAN-14-2030 Cancer Therapeutics, Targets, and Chemical Biology Research Harnessing the Fcm Receptor for Potent and Selective Cytotoxic Therapy of Chronic Lymphocytic Leukemia Bereng ere Vire1, Martin Skarzynski1, Joshua D. Thomas2, Christopher G. Nelson2, Alexandre David3, Georg Aue1, Terrence R. Burke Jr2, Christoph Rader4,5,6, and Adrian Wiestner1 Abstract Chronic lymphocytic leukemia (CLL) is a B-cell malignancy in need of new, effective, and safe therapies. The recently identified IgM receptor FcmR is overexpressed on malignant B cells in CLL and mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fcm). To exploit this internalization and trafficking pathway for targeted drug delivery, we engineered an IgM-derived protein scaffold (Fcm) and linked it with the cytotoxic agent monomethylauristatin F. This Fcm–drug conjugate was selectively toxic for FcmR- expressing cell lines in vitro and for CLL cells but not autologous normal T cells ex vivo. Notably, the cytotoxic activity of the Fcm–drug conjugate was maintained in CLL cells carrying a 17p deletion, which predicts resistance to standard chemotherapy. Next, we tested the possible therapeutic application of the Fcm–drug conjugate in immunodeficient NOD/SCID/IL-2Rgnull (NSG) mice engrafted with peripheral blood cells from patients with leukemia. Three intravenous injections of the Fcm–drug conjugate over a 10-day period were well tolerated and selectively killed the human CLL cells but not the coengrafted autologous human T cells. In summary, we developed a novel strategy for targeted cytotoxic therapy of CLL based on the unique properties of FcmR. FcmR- targeted drug delivery showed potent and specific therapeutic activity in CLL, thus providing proof of concept for FcmR as a valuable therapeutic target in CLL and for IgM-based antibody–drug conjugates as a new targeting platform. Cancer Res; 74(24); 7510–20. Ó2014 AACR. Introduction normal cells. The Food and Drug Administration (FDA) On the basis of their ability to selectively deliver highly approval of brentuximab vedotin for the therapy of Hodgkin lymphoma and anaplastic large cell lymphoma in 2011 and of cytotoxic drugs into tumor cells, antibody–drug conjugates þ (ADC) are among the most promising next-generation anti- trastuzumab emtansine for HER2 metastatic breast cancer in body therapeutics for cancer therapy (1, 2). The promise of 2013 were milestones that established the therapeutic utility of ADCs is the targeted delivery of a potent cytotoxic drug ADCs (3, 4). Brentuximab vedotin consists of a chimeric selectively into tumor cells, thereby minimizing toxicity toward mouse/human anti-human CD30 monoclonal antibody (mAb) in IgG1 format as the carrier protein conjugated to mono- methylauristatin E (MMAE) as the cytotoxic payload (5). MMAE is a synthetic antitubulin agent active at subnanomolar 1Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. 2Chemical Biology Laboratory, Molecular Discovery concentrations. Each MMAE drug is linked to the antibody Program, Center for Cancer Research, National Cancer Institute, NIH, molecule through a linker that harbors a valine–citrulline– 3 Frederick, Maryland. Laboratory of Viral Diseases, National Institute of para-aminobenzylcarbamate (Val–Cit–PABC) linker that is Allergy and Infectious Diseases, NIH, Bethesda, Maryland. 4Experimental Transplantation and Immunology Branch, Center for Cancer Research, cleaved by lysosomal proteases such as cathepsin B. The linker National Cancer Institute, NIH, Bethesda, Maryland. 5Department of Can- also contains a maleimide group that reacts with thiol groups cer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, in the IgG1 hinge region. This random conjugation results in an Florida. 6Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida. ADC mixture with an average drug-to-antibody ratio (DAR) of 4:1 (range, 0:1 to 8:1). Trastuzumab emtansine is based on the Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). humanized anti-human HER2 mAb trastuzumab randomly conjugated to an average of 3.5 maytansinoid drugs through B. Vire and M. Skarzynski contributed equally to this article. the e-amino group of lysine (Lys) using a noncleavable linker Corresponding Authors: Adrian Wiestner, Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Building 10, CRC (6). This new generation of ADCs has demonstrated two 3-5140, 10 Center Drive, Bethesda, MD 20892-1202. Phone: 301-594- important treatment advances; first, patients who relapse or 6855; Fax: 301-496-8396; E-mail: [email protected]; and Christoph are refractory to first-line therapy can be rescued using tar- Rader, Department of Cancer Biology, Department of Molecular Thera- peutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way geted cytotoxic drug delivery; and second, an ADC can replace #2C1, Jupiter, FL 33458. Phone: 561-228-2053; Fax: 561-228-2169; systemic cytotoxic therapy demonstrating higher efficacy with E-mail: [email protected] lower toxicity (7, 8). doi: 10.1158/0008-5472.CAN-14-2030 Chronic lymphocytic leukemia (CLL), the most common Ó2014 American Association for Cancer Research. leukemia in Western countries, is characterized by the 7510 Cancer Res; 74(24) December 15, 2014 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst October 24, 2014; DOI: 10.1158/0008-5472.CAN-14-2030 Targeted Cytotoxic Drug Delivery through the Fcm Receptor accumulation of mature monoclonal B cells in the blood, bone more readily undergo apoptosis. FcmR is overexpressed on the marrow, spleen, and lymph nodes. The median age at diagnosis CLL B cells compared with B cells from normal donors and is 75 years, precluding use of allogeneic hematopoietic stem compared with the nonclonal T cells in the blood of patients cell transplantation, the only curative treatment option, in the with CLL. FcmR may play a role in the pathogenesis of CLL, majority of patients. Current first-line treatment is chemoim- possibly by contributing to concomitant BCR and Toll-like munotherapy with an anti-CD20 mAb and an alkylating agent receptor (TLR) activation that could enhance leukemic cell with or without the addition of a purine analog (9–11). One of proliferation and survival (26, 31, 32). However, exactly what the most commonly used regimens for younger patients is the functional role, if any, FcmR has in the pathogenesis of CLL combination of fludarabine, cyclophosphamide, and rituximab remains to be defined. (FCR; refs. 11, 12). Although initial response rates are high, Fc receptors are highly effective in targeting specific mole- most patients relapse. FCR is less active in high-risk disease, cules for binding to and internalization into select target cells. less tolerable in elderly or frail patients, and increases the risk The existence of a variety of distinct Fc receptors with restrict- of infections. Fludarabine and cyclophosphamide are also toxic ed cellular expression provides the basis for selective targeting for normal T cells and myeloid cells, leading to often long- approaches. For example, FcgRIII on dendritic cells has been lasting cytopenias. In contrast, the anti-CD20 mAbs rituximab, used for internalization of vaccine components (33). However, ofatumumab, and obinutuzumab selectively target B cells (13). delivering cytotoxic agents through Fc receptor–mediated These mAbs induce cell death mostly through immunologic internalization as anticancer therapy has not been established. effector mechanisms such as complement-dependent cytotox- In previous work, we have shown that FcmR on CLL cells is icity and antibody-dependent cellular cytotoxicity (13, 14). As functional, rapidly internalizes IgM, and delivers it to the single agents, the efficacy of anti-CD20 mAbs in CLL is limited lysosome where it is degraded (26). In fact, more than 50% of and they are used primarily in combination regimens. Notably, IgM bound to the CLL cell surface is internalized via FcmR CD20 is expressed at higher levels on normal B cells than on within 1 minute, and internalization is complete by 5 minutes. CLL cells (15), and anti-CD20 mAbs effectively kill normal B We hypothesized that the overexpression of FcmR on CLL cells cells, potentially contributing to life-threatening viral, bacte- and its ability to internalize bound IgM could be used for rial, and fungal infections (16). Recently, kinase inhibitors that targeted delivery of antileukemic therapy. target B-cell receptor (BCR) signal transduction have shown Here, we describe the derivation of an FcmR-targeting strat- impressive clinical activity in CLL (17–19). However, while well egy that can deliver a cytotoxic payload selectively into CLL tolerated as single agents, these inhibitors achieve mostly cells and show that it has antitumor activity against primary partial responses and have to be taken continuously. In fact, human tumor cells in vivo. On the basis of the work by even after years of treatment with a kinase inhibitor, residual Kubagawa and colleagues (23), we knew that binding of IgM disease is easily detected in virtually all patients and resistant to FcmR critically depends on the integrity of sequences in the clones emerge that lead to relapse. Thus, there is a great clinical
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