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Single-Dose Versus Fractionated Radioimmunotherapy of Human Colon Carcinoma Xenografts Using 131I-Labeled Multivalent CC49 Single-Chain Fvs1

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Single-Dose Versus Fractionated Radioimmunotherapy of Human Colon Carcinoma Xenografts Using 131I-Labeled Multivalent CC49 Single-Chain Fvs1 Vol. 7, 175–184, January 2001 Clinical Cancer Research 175 Single-Dose versus Fractionated Radioimmunotherapy of Human Colon Carcinoma Xenografts Using 131I-labeled Multivalent CC49 Single-chain Fvs1 Apollina Goel, Sam Augustine, labeled systemic toxicity was observed in any treatment Janina Baranowska-Kortylewicz, David Colcher, groups. The results show that radioimmunotherapy delivery for sc(Fv) and [sc(Fv) ] in a fractionated schedule clearly Barbara J. M. Booth, Gabriela Pavlinkova, 2 2 2 2 presented a therapeutic advantage over single administration. Margaret Tempero, and Surinder K. Batra The treatment group receiving tetravalent scFv showed a sta- Departments of Biochemistry and Molecular Biology [A. G., tistically significant prolonged survival with both single and S. K. B.], Pathology and Microbiology [S. A., B. J. M. B., G. P., fractionated administrations suggesting a promising prospect S. K. B.], and Radiation Oncology [J. B-K.], College of Pharmacy [S. A.], Eppley Institute for Research in Cancer and Allied Diseases of this reagent for cancer therapy and diagnosis in MAb-based [S. K. B.], University of Nebraska Medical Center, Omaha, Nebraska radiopharmaceuticals. 68198; Coulter Pharmaceutical Incorporated, San Francisco, California 94080 [D. C.]; and University of California San Francisco Cancer Center, San Francisco, California 94115 [M. T.] INTRODUCTION RIT3 is a rapidly developing therapeutic modality for the treatment of a wide variety of carcinomas (1). Numerous anti- ABSTRACT body-radionuclide combinations have been evaluated in clinical The prospects of radiolabeled antibodies in cancer detec- studies (2–9). RIT has yielded complete responses in hemato- tion and therapy remain promising. However, efforts to logical diseases like Hodgkin and non-Hodgkin lymphoma (10, achieve cures, especially of solid tumors, with the systemic 11); however, for solid tumors only a partial clinical response administration of radiolabeled monoclonal antibodies (MAbs) has been observed (12–14). Methods for improving the thera- have met with limited success. Using genetic engineering tech- peutic index (tumor:normal tissue ratio) remain to be optimized niques, MAbs have been tailored to improve the therapeutic for the development of more effective RIT for solid tumors (15). index (tumor:normal tissue ratio) in clinical radioimmuno- Most of the radioimmunoconjugates studied to date involve therapy. In the present study, we investigated the potential of the use of whole immunoglobulins, particularly IgG. Intact ϳ tetravalent {[sc(Fv)2]2} and divalent [sc(Fv)2] single chain Fvs MAbs (Mr 150,000) remain in circulation for an extended time of MAb CC49 for therapy in athymic mice bearing s.c. LS- and can therefore increase the radiation dose delivered to normal 174T human colon carcinoma xenografts. Mice received 1000 tissues (16). Moreover, the poor tumor penetration of MAbs ␮ 131 131 Ci of I-labeled [sc(Fv)2]2 or I-labeled sc(Fv)2, either as a results in the localization of only 0.0001–0.01%ID/g of tumor single injection on day 6 or as four injections (250 ␮Ci each) on (17). Many solid tumors are relatively radioresistant; therefore, days 6, 7, 8, and 9; the day of tumor implantation was taken as RIT of such tumors requires high radiation doses, which can day 0. The median survival for the control group was 26 days. result in significant nonspecific uptake by normal tissue leading Comparisons of single and fractionated therapeutic regimens to toxicity, especially to the hematopoietic system (18). Because showed median survival as 32 (P < 0.001) and 53 days (P < the size of the antibody-based molecule relative to the renal 0.0001), respectively for [sc(Fv)2]2 and 26 (P > 0.5) and 38 days threshold for first-pass clearance is a major factor in determin- (P < 0.0001), respectively for sc(Fv)2 when compared with the ing the residence time of the radioimmunoconjugate in circula- Ј Ј control groups. The time for the quadrupling of tumor volume tion, a range of IgG formats, like F(ab )2, Fab , or Fab, have (for single and fractionated therapeutic treatments were: 9.0 ؎ been investigated for therapeutic potential at preclinical (19–21 ؎ ؎ 0.8 and 21.1 2.9 days respectively for sc(Fv)2; 16.6 1.9 and and clinical levels (5, 22, 23). Decreasing the size of the anti- ؎ ؎ 32.9 2.7 days respectively for [sc(Fv)2]2; and 8.3 0.7 and body molecule increased both the degree of penetration and the days respectively for the control group. No 131I- clearance rate from the blood pool; however, these molecules 0.6 ؎ 8.4 were difficult to generate at a large scale with clinical-grade purity and did not provide a significant increment in quantitative tumor retention as an intact antibody (24). Received 7/26/00; revised 10/18/00; accepted 10/18/00. The advent of molecular biology has enabled the designing The costs of publication of this article were defrayed in part by the and purification in ample abundance of small, high-affinity, payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by grants from the United States Department of Energy (DE-FG02-95ER62024) and NIH (P5O CA72712 and RO1 CA78590). 3 The abbreviations used are: RIT, radioimmunotherapy; scFv, single 2 To whom requests for reprints should be addressed, at Department of chain Fv; sc(Fv)2, covalent divalent scFv; [sc(Fv)2]2, noncovalent tet- Biochemistry and Molecular Biology, Eppley Institute for Research in ravalent scFv; HPLC, high performance liquid chromatography; MAbs, Cancer and Allied Diseases, University of Nebraska Medical Center, monoclonal antibodies; SPR, surface plasmon resonance; BSM, bovine 984525 Nebraska Medical Center, Omaha, NE 68198-4525. Phone: submaxillary gland mucin; %ID/g, % of injected dose/g; RI, radiolocal- (402) 559-5455; Fax: (402) 559-6650; E-mail: [email protected]. ization index; VL, variable light chain; VH, variable heavy chain. Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2001 American Association for Cancer Research. 176 Therapeutic Efficacy of 131I-labeled Multivalent CC49 scFvs for Colon Carcinoma multivalent antibody-based molecules as carriers for radionu- Hercules, CA). The elution was monitored by an in-line UV clides (25). ScFvs are recombinant proteins composed of a VL detector at 280 nm. amino acid sequence of an immunoglobulin tethered to a VH The immunoreactivity of scFvs was analyzed by a solid sequence by a designed peptide (26, 27). Compared with an phase competition ELISA using BSM (Sigma Chemical Co., St. intact antibody, scFvs can bind to a tumor cell in a more Louis, MO) as the antigen (36). The binding affinities of homogeneous distribution (28, 29). Such fragments lead to a sc(Fv)2, [sc(Fv)2]2, and CC49 IgG for BSM were determined by higher tumor:normal tissue ratio, but the percentage of injected SPR measurements using an upgraded version of BIAcore 1000 dose delivered to the tumor is usually poor because of their (Pharmacia Biosensor, Uppsala, Sweden) as described previ- monovalent nature and faster removal from the circulatory sys- ously (36, 44). The kinetic rate constants (kon and koff) were tem. Moreover, the high renal accretion of these small mole- measured, and the equilibrium association constant (KA) and cules can lead to severe nephrotoxicity at therapeutic doses (24). equilibrium dissociation constant (KD) were derived. To increase the functional affinity of scFvs, the valency of scFvs Radioiodination of scFvs. The scFv forms were labeled 125 131 has been increased by connecting them together by either non- with either Na IorNa I using 1,3,4,6-tetrachloro-3␣,6␣- covalent or covalent interactions (28–30). The divalent scFvs diphenylglycoluril (IodoGen; Pierce Chemical Co., Rockford, have shown improved avidity and efficacy for tumor targeting at IL) as the oxidant (45). For therapeutic labeling, iodinations 131 preclinical levels (31–36). were carried out with 15–20 mCi of Na I (NEN, Boston, CC49 is a second-generation murine MAb showing high MA)/mg of scFvs in 0.1 M sodium phosphate buffer (pH 7.2) affinity for the tumor-associated glycoprotein 72 (37). CC49 with IodoGen (250 ␮g/mg of protein) and at a protein concen- MAb is under clinical trials for radiation-mediated therapy of tration of 2–3 mg/ml. Unincorporated radioiodine was separated ovarian, colorectal, breast, and prostate carcinoma (4, 38–41). from the labeled protein by size exclusion chromatography In the present study, we have investigated for the first time the using a Sephadex G25 column (Pharmacia, Piscataway, NJ). The specific activity of 125I- and 131I-labeled scFv molecules therapeutic potential of divalent [sc(Fv)2] and tetravalent was about 3–9 mCi/mg. The radiochemical purity of all of the {[sc(Fv)2]2} CC49 scFvs under single and dose-fractionation schedules in athymic mice bearing human colon carcinoma radiolabeled scFvs was Ն98% as confirmed by ITLC. xenografts. Fractionated therapeutic treatment was found to be Characterization of Radiolabeled scFvs. Radiolabeled proteins were analyzed on SDS-PAGE gels, and the radioactiv- clearly superior to single administration for both sc(Fv)2 and ity associated with the protein was measured using the Image- [sc(Fv)2]2. We believe that the multivalent CC49 scFvs hold potential toward the generation of optimum tumor-targeting Quant software of the PhosphorImager (Molecular Dynamics, reagents in radionuclide-mediated therapy. Sunnyvale, CA). Analytical size-exclusion HPLC was per- formed as described above. Fractions (1 ml) of the radiolabeled protein were collected, and the radioactivity was determined in MATERIALS AND METHODS a Packard Minaxi Auto-Gamma 5000 gamma counter (Meriden, Protein Expression and Purification. For functional CT). The immunoreactivity of radiolabeled CC49 scFv forms expression of the divalent and tetravalent CC49 scFvs, the was assessed by RIA where BSM (surrogate for TAG-72 anti- construct (VL-linker-VH-linker-VL-linker-VH-His6) was cloned gen) and BSA (negative control) were attached to a solid-phase in the yeast shuttle vector, pPICZ␣A (Invitrogen, Carlsbad, CA) matrix (Reacti-Gel HW-65F; Pierce; Ref.
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