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The Humoral Immune Response to Macrocyclic Chelating Agent DOTA Depends on the Carrier Molecule

Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan; and Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy

The chelating agent 1,4,7,10-tetraazacyclododecane-N,N', N'',N'''-tetraacetic acid (DOTA) is used to label monoclonal antibodies (mAbs) and peptides with ⁹⁰Y. DOTA allows the generation of clinically useful stable metallic radioconjugates for the treatment of a variety of tumors, but its immunogenicity has remained controversial. In this study, we evaluated the immune response to DOTA in a preclinical mouse model and in patients entered in a clinical trial. Methods: Sera were obtained from BALB/c mice injected intraperitoneally or subcutaneously with different doses and formulations of syngeneic and xenogeneic mAbs or peptide (murine mAb Mov19 [mM19]; its chimeric version; murine V/human C ChiMov19 [cM19]; or Tyr³-octreotide)-DOTA conjugates. Sera from patients with neuroendocrine tumors, enrolled in a protocol for somatostatin receptor–mediated radionuclide therapy with ⁹⁰Y-DOTA-D-Phe¹-Tyr³-octreotide (DOTATOC), were also collected before and after each treatment. Levels and specificity of antibody response to relevant (Mov19, ChiMov19, or Tyr³-octreotide) and nonrelevant (human serum albumin) DOTA targets were tested by enzyme-linked immunosorbent assay and competition assays. An anti-DOTA mAb (IgG1) derived from a ChiMov19-DOTA immunized mouse was used, in a competitive radioimmunoassay, to determine the efficiency of DOTA presentation on the different carriers. Results: Depending on the immunogenicity and dosage of the mAb, a specific anti-DOTA response was revealed in the preclinical system. However, DOTA–peptide conjugate induced no immune-detectable response against either chelator or carrier. DOTA was poorly presented on small peptides, as determined using the anti-DOTA mAb. Conclusion: A humoral response against DOTA is possible, but only as a consequence of the response elicited against the carrier. Octreotide was not immunogenic. Thus, ⁹⁰Y-DOTATOC can be considered a safe and useful tool for receptor-mediated radionuclide therapy of somatostatin receptor–overexpressing tumors.

Key Words: DOTA • immunogenicity • antimacrocyclic antibodies • receptor-mediated radionuclide therapy