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Improved Therapeutic Results by Pretargeted Radioimmunotherapy of Non–Hodgkin's Lymphoma with a New Recombinant, Trivalent, Anti-CD20, Bispecific Antibody

¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey; ² Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ³ IBC Pharmaceuticals, Inc.; ⁴ Immunomedics, Inc., Morris Plains, New Jersey

Requests for reprints: Robert M. Sharkey, Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7121; Fax: 973-844-7020; E-mail: rmsharkey{at}gscancer.org.

Key Words: bispecific antibody • non–Hodgkin's lymphoma • pretargeting • radioimmunotherapy

We examined whether a pretargeting method using a new recombinant anti-CD20 bispecific antibody (bsMAb) followed by ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (⁹⁰Y-DOTA)-peptide could reduce hematologic toxicity yet improve therapeutic responses compared with conventional ⁹⁰Y-anti-CD20 IgG and a chemically conjugated bsMAb. TF4, a humanized, tri-Fab bsMAb with two Fabs binding CD20 and one Fab binding histamine-succinyl-glycine (HSG), developed by the dock and lock (DNL) method, was tested in nude mice with Ramos B-cell lymphomas. Optimal pretargeting required a 29-h interval between TF4 and ⁹⁰Y-DOTA-HSG, and 20-fold more moles of TF4. TF4 cleared more rapidly from the blood than anti-CD20 IgG, with early processing in the liver, spleen, and kidney. At 24 h, TF4 improved tumor uptake of ¹¹¹In-HSG-peptide 2.6-fold [13% versus 5% injected dose per gram (ID/g)] and enhanced tumor to blood ratios >45-fold (770 versus 17), compared with an anti-CD20 Fab x anti-HSG Fab chemical conjugate, and by 1.6-fold (9.0% versus 5.6% ID/g) and 1,600-fold (522 versus 0.32), respectively, compared with radiolabeled anti-CD20 IgG. A severe (90%) and prolonged reduction of WBCs was observed at the maximum dose of ⁹⁰Y-anti-CD20 IgG, whereas pretargeting resulted in a 60% transient drop. TF4 pretargeting resulted in highly significant improvement in survival, curing 33% to 90% of the animals, even at relatively low doses, whereas most tumors progressed quickly without cures with ⁹⁰Y-anti-CD20 IgG. These results indicate an improved therapeutic index with pretargeted radioimmunotherapy (RAIT) using a DNL-constructed tri-Fab, bsMAb, compared with conventional therapy with directly radiolabeled antibody or with a chemically conjugated bsMAb. These encouraging results prompt testing these constructs for pretargeting RAIT in patients. [Cancer Res 2008;68(13):5282–90]