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Development of meta-Tetrahydroxyphenylchlorin-Monoclonal Antibody Conjugates for Photoimmunotherapy

Departments of Otolaryngology/Head and Neck Surgery [M. B. V., M. S., G. B. S., G. A. M. S. v. D.] and Pulmonology [P. E. P.], Free University Hospital; Radio Nuclide Center, Free University [G. W. M. V.]; and Division of Experimental Therapy, Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis [F. A. S., H. O.], 1081 HV Amsterdam, The Netherlands

A limitation of photodynamic therapy is the lack of tumor selectivity of the photosensitizer. To overcome this problem, a protocol was developed for coupling of meta-tetrahydroxyphenylchlorin (mTHPC), one of the most promising photosensitizers, to tumor-selective monoclonal antibodies (MAbs). mTHPC was radiolabeled with ¹³¹I to facilitate the assessment of the in vitro and in vivo behavior. After the modification to ¹³¹I-mTHPC-(CH₂COOH)₄, thus increasing the water solubility and creating a functional moiety suitable for coupling, conjugation was performed using a labile ester. Insoluble aggregates were not formed when mTHPC-MAb conjugates with a molar ratio of up to 4 were prepared. These conjugates showed a minimal impairment of the integrity on SDS-PAGE, full stability in serum in vitro, and an optimal immunoreactivity.

To test the in vivo behavior of the mTHPC-MAb conjugates, the head and neck squamous cell carcinoma-selective chimeric MAb U36 was used in head and neck squamous cell carcinoma-bearing nude mice. Biodistribution data showed that the tumor selectivity of cMAb U36-conjugated mTHPC was increased in comparison with free mTHPC, despite the fact that conjugates with a higher mTHPC:MAb ratio were more rapidly cleared from the blood. Preliminary results on the in vitro efficacy of photodynamic therapy with MAb-conjugated mTHPC showed that mTHPC coupled to the internalizing murine MAb 425 exhibited more phototoxicity than when coupled to the noninternalizing chimeric MAb U36.

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