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Comparative Localization of Murine Monoclonal Antibody Me1-14 F(ab')₂ Fragment and Whole IgG2a in Human Glioma Xenografts¹

Departments of Pathology [E. V. C., P. A. H., M. R. Z., D. D. B.] Pediatrics [H. S. F.], and Radiology [M. R. Z.] and the Preuss Laboratory for Brain Tumor Research [D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; Department of Neurology, Northwestern University Medical School, Evanston Hospital, Evanston, Illinois 60201 [D. R. G.]; Department of Neurosurgery, Central University Hospital Vaudois, CH-1011 Lausanne, Switzerland [N. T.]; and Ludwig Institute for Cancer Research, Lausanne Branch, CH-1066 Epalinges, Switzerland [S. C.]

Monoclonal antibodies (MAbs) targeted to glioma-associated antigens may allow the selective delivery of imaging and therapeutic agents to brain tumors; the use of MAb fragments may be a strategy to further improve tumor uptake of such agents relative to normal tissues. In this study, we have examined the in vivo localization of radioiodinated MAb Me1-14, a murine immunoglobulin G2a (IgG2a) reactive with gliomas, and its F(ab')₂ fragment in s.c. and intracranial xenografts of human glioma cell line D-54 MG in athymic mice. The radiolabeled F(ab')₂ fragment of Me1-14 was demonstrated to possess in vitro binding affinity and immunoreactivity comparable to that of whole IgG. Direct comparison of IgG and F(ab')₂ biodistribution in s. c. xenograft-bearing mice showed higher tumor: normal tissue ratios of the F(ab')₂ fragment compared to IgG. In intracranial tumor-bearing mice paired-label analysis using a nonspecific protein control showed earlier specific tumor localization by the F(ab')₂ fragment of Me1-14 compared to IgG. Blood-to-tumor transfer constants (K₁) derived for Me1-14 F(ab')₂ were significantly greater than those for whole Me1-14 (P = 0.01). Estimated radiation dosimetry revealed that ¹³¹I-labeled Me1-14 F(ab')₂ would deliver higher radiation doses to tumor than to normal tissues. These studies demonstrate that the F(ab')₂ fragment of Me1-14 may be a potential agent for immune-directed brain tumor diagnosis and therapy.

¹ This work was supported by NIH Grants CA42324, CA11898, CA32672, CA44640, NS12745, NS20023, K07NS00958, K04NS00814, and ACS CH403.

² Recipient of a Fellowship of the Medical Research Council of Canada.

³ To whom requests for reprints should be addressed, at Box 3156, Duke University Medical Center, Durham, NC 27710.

Received 3/25/88. Revised 6/24/88. Accepted 7/18/88.

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