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Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I

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Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I Vol. 5, 3065s-3072s, October 1999 (Suppl.) Clinical Cancer Research 3065s Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I J. Burton, z D. Mishina, T. Cardillo, K. Lew, cGy/mCi of injected dose compared with 3099 cGy/mCi of A. Rubin, D. M. Goldenberg, and D. V. Gold tumor-absorbed dose delivered by nonspecific antibody. Garden State Cancer Center, Belleville, New Jersey 07109 [J. B., D. M., T. C., K. L., D. M. G., D. V. G.], and St. Joseph's Hospital and Introduction Medical Center, Paterson, New Jersey 07503 [A. R.] MM 3 is a B-cell malignancy that appears to result from the transformation and monoclonal expansion of a cell with char- acteristics of a plasma cell, i.e., a terminally differentiated B cell Abstract (1, 2). The expression by MM cells of certain non-B-cell anti- Multiple myeloma (MM) is the second most common gens also raises the possibility of the transformation of an hematological cancer in the United States. It is typically earlier, more multipotent lymphoid precursor cell. As with nor- incurable, even with myeloablative chemotherapy and stem- mal plasma cells, this degree of terminal differentiation is as- cell transplantation. The epithelial mucin-1 (MUC1) glyco- sociated with the complete or partial loss of certain B-cell- protein is expressed by normal and malignant epithelial cells associated antigens, such as surface immunoglobulin and CDs but has also been shown to be expressed by MM cells. MUC1 19-22 (CD19 is expressed on normal plasma cells; Ref. 3). In is a useful antigenic target in solid tumors for clinical diag- addition, there is the acquisition of selected non-B-cell-specific nostic and therapeutic monoclonal antibody (mAb)-based markers, such as CD28, CD38, and CD56; epithelial antigens approaches. The MA5 mAb, as well as other anti-MUC1 such as syndecan-1 (CD138) and epithelial glycoprotein-2; cer- mAbs reactive with the MUC1 variable number tandem tain myeloid antigens; and the antigen addressed in this report, repeat domain, exhibited moderate to strong reactivity with MUC1 (4-11). MUC1 is of particular interest because it is a both MM cell lines and clinical samples. To explore the diagnostic marker that exists as an integral membrane glyco- biochemical nature and potential of MUC1 as an antigenic protein and as shed forms and because it is a therapeutic target target in MM, studies were performed to: (a) compare the for both cell-mediated and antibody-based immunotherapeutic mRNA and the MUC1 glycoprotein species between epithe- strategies. Although no function has yet been determined for lial cancer and MM cell lines; and (b) develop and use a membrane-bound MUC1, a receptor/ligand-binding property human MM tumor xenograft model system to study the has been associated with neoplastic progression and cellular biodistribution of the MA5 mAb. MA5 mAb was strongly adhesion (12). Although most of the work to date with this target reactive with six of eight human MM cell lines by flow antigen has been in breast and pancreatic cancers, a few reports cytometry. In seven of eight MM patient samples (bone have shown that MUC1 can be detected in the serum of MM marrow and/or peripheral blood) reactivity was found in patients and, thus, may also represent a surrogate tumor marker 10-90% of the cells, whereas normal control (n = 5) and in MM (10). leukemia and lymphoma (n = 5) cells showed only 0-6% Progress in the therapy of MM has been achieved over the reactivity, lzsI-labeled MA5 whole-cell binding studies past 25 years with the introduction of chemotherapy regimens, showed quantitatively similar amounts of binding between resulting in objective antitumor effects (1, 2, 13-15). Some strongly positive MM lines and high-MUCl-expressing additional therapeutic benefit has resulted from the more recent breast carcinoma lines, mRNA expression was assessed by application of high-dose chemotherapy with autologous or al- Northern blotting and reverse transcription-PCR. MM cell logeneic stem-cell rescue (14, 15). Nonetheless, MM remains lines were positive by both methods, with strong similarity in fairly resistant to all of these approaches in the majority of cases. the sizes of the mRNAs and cDNAs that were obtained. Long-term survival, in fact, has not improved much since the Finally, biodistribution experiments were carried out with advent of chemotherapy with phenylalanine mustard (Melpha- 13~I-labeled MA5 versus a nonbinding control 12SI-labeled lan) and glucocorticoids. Drug resistance mechanisms via mul- mAb in a s.c. MM xenograft model. Selective MM tumor tidrug resistance protein 1 and lung resistance-related protein uptake of the MA5 mAb was demonstrated, with a potential have been described in MM and appear to be major mechanisms for delivering a tumor radiation absorbed dose of 8540 of resistance to therapy (16-18). Multidrug resistance protein 1 expression may be intrinsic to both malignant and nonmalignant 1 Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. 3 The abbreviations used are: MM, multiple myeloma; CD, cluster of Supported in part by USPHS Grants CA54425 and CA39841 from the differentiation; MUC1, epithelial mucin-1, polymorphic epithelial mu- NIH. cin or epithelial membrane antigen; RAIT, radioimmunotherapy; mAb, 2 To whom requests for reprints should be addressed, at Garden State monoclonal antibody; ATCC, American Tissue Culture Collection; RT- Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109. Phone: PCR, reverse transcription-PCR; VNTR, variable number tandem re- 973-844-7024; Fax: 973-844-7020. peat; %iD/g, percentage of injected dose per gram. Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 1999 American Association for Cancer Research. 3066s MA5 Anti-MUC 1 mAb Targeting of Multiple Myeloma plasma cells because cell surface expression of this transporter Newark, N J). Mononuclear cells were isolated from bone mar- protein was found in 42 of 43 samples, which included 19 row by density gradient centrifugation (Cell-Sep; Larex, Inc., St. patients with either monoclonal gammopathy of undetermined Paul, MN). significance or amyloidosis (17). Lung resistance-related protein RT-PCR and Northern Blotting. The starting template expression was shown to be an important factor in determining material for RT-PCR was total RNA, which was isolated from response to standard-dose Melphalan-prednisone (18). The ex- PBS-washed cells that were solubilized with a guanidine iso- pression levels of the antiapoptotic protein BCL-XL has also thiocyanate-based buffer (Tri-Reagent; Sigma-Aldrich, St. been shown to play a role in determining chemoresistance, with Louis, MO). RNA was isolated according to a modification of increased levels leading to relative drug resistance (19). BCL-2 the method of Chomczynski and Mackey (29). Total RNA (5 may also play a role in chemoresistance in MM (20). Other Ixg) was used as the template for cDNA synthesis, using the factors, such as mutations in the ras oncogene or the p53 gene, First Strand kit of Novagen (Madison, WI) according to manu- are not common enough to play a major role in MM pathophys- facturer's instructions, with 4% of the resulting cDNA product iology (21, 22). The tendency toward chemoresistance, along being used as template for each PCR reaction. Primers and with the relative clinical radiosensitivity of MM (23-25), sug- dNTPs were added at standard concentrations, 0.5 and 200 lxM, gests that MM would be a favorable target for RAIT. The respectively. Thermostable DNA polymerase (0.5 p,l; KlenTaq; predominant involvement of the red marrow in MM lends Ab Peptides, St. Louis, MO) was added to each tube, and 35 further support to RAIT approaches because mAb uptake is both cycles of PCR were carried out under the following conditions: rapid and high in the bone marrow compartment. Indeed, pre- annealing temp of 65~ for 45 s, extension at 72~ for 30 s, and clinical experiments in immunotherapy and radioimmunotarget- denaturation at 94~ for 30 s (initial denaturation was at 94~ ing in a MM model system have shown potential for these for 2 rain). mAb-mediated approaches (26, 27). In addition, another ap- Total RNA (20 p~g) from selected cell lines was denatured proach has been developed to selectively deliver radiation doses in a 50% formamide-2.2 M formaldehyde solution, fractionated to the red marrow in MM through the use of a bone-seeking by electrophoresis through a 0.8% agarose gel containing 0.66 M radionuclide, 166H0. Initial clinical studies have demonstrated formaldehyde and transferred onto a nylon membrane (Hybond; that radiation doses of up to -5000 cGy can be safely delivered Amersham Corp., Chicago, IL) by capillary blotting. RNA was to the marrow cavity by this approach (28). fixed by baking at 80~ under vacuum. After prehybridization Given the above background, we sought in the studies at room temperature in a solution containing 5• SSC buffer reported herein to address selected questions regarding MUC1 plus 0.2 M sodium phosphate (pH 6.8), 1 • Denhardt's reagent, expression in MM that had not been fully addressed previously. 50% formamide, 100 txg/ml sheared salmon sperm DNA, 50 These questions are: (a) What mRNA species are expressed by pLg/ml yeast tRNA, and 20 Ixg/ml poly(A) n, the membrane was MM cell lines? (b) What is the general sequence structure of hybridized with the labeled MUC1 probe at 42~ for 14-16 h. MUCI cDNA in MM? (c) Is MUC 1 a target antigen that can be The probe was labeled with [oL-32p]-dCTP by the nick transla- effectively used in preclinical MM tumor xenograft biodistribu- tion method, according to the manufacturer's instructions (Am- tion studies? ersham).
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