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Development of Humoral Immune Responses against a Macrocyclic Chelating Agent (DOTA) in Cancer Patients Receiving Radioimmunoconjugates for Imaging and Therapy¹

Imperial Cancer Research Fund Oncology Group and Department of Clinical Oncology [C. K., D. S., C. S. G., N. S. C-L., A. A. E.], Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, United Kingdom, and Department of Chemistry [M. J. M., C. F. M.], University of California, Davis, California 95616

The development of stable immunoconjugates by the advent of macrocyclic metal chelating agents (DOTA) has enabled us to study the ability of ¹¹¹In-DOTA-labeled monoclonal antibodies to detect tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered ⁹⁰Y-DOTA-labeled murine monoclonal antibody in a Phase I/II clinical trial of advanced ovarian cancer. The development of serum sickness-like reactions in three of six treated patients, in the absence of previous monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate.

Six patients with ovarian cancer received 25 mg of HMFG1 monoclonal antibody coupled with ⁹⁰Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant tumors received low doses (220 µg to 1 mg) of monoclonal antibodies, labeled with ¹¹¹In-DOTA, i.v. for imaging studies.

Using a solid-phase enzyme-linked immunosorbent assay method, the immunogenicity of DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or therapy with DOTA-coupled monoclonal antibodies, as well as sera from patients who did not receive DOTA-coupled antibody, were screened on enzyme-linked immunosorbent assay plates coated with human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p. monoclonal antibody developed anti-DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of DOTA-coupled monoclonal antibody developed antibodies against DOTA. The levels of anti-DOTA response correlated with the amount of injected radioimmunoconjugate (r = 0.889, P < 0.001). None of the patients who received DOTA-coupled antibody had detectable antibodies against the macrocycle before immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to DOTA. Most, if not all, of the immune response is directed against the DOTA ring structure. Affinity purification of anti-DOTA antibody from serum enabled quantitation of these antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to DOTA, by HSA-2-iminothiolane-DOTA (100 µg/ml) and the level of anti-DOTA immunoglobulin in the serum.

We conclude that the new chelate p-nitro-benzyl-DOTA, although it can produce stable radioimmunoconjugates for in vivo use, leads to the development of immune responses in patients, as a hapten on a carrier protein (antibody), at doses of immunoconjugate > 200 µg and can lead to serum sickness-like clinical reactions, when administered i.p. at therapeutic doses with up to 5% aggregates in the preparations.

¹ Supported by a grant from the State Scholarships Foundation of Greece (to C. K.). The work in preparing DOTA was supported by an NIH grant (CA 16861 to C. F. M.). The present work was presented in part as an abstract at the Sixth International Conference on Monoclonal Antibody Immunoconjugates for Cancer, San Diego CA, February 27 to March 2, 1991.

² To whom requests for reprints should be addressed, at ICRF Oncology Group, Department of Clinical Oncology, 3rd Floor MRC Bldg., Hammersmith Hospital, Du Cane Road, London W12 ONN, England.

Received 9/ 4/91. Accepted 11/22/91.

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