The humoral immune response to macrocyclic chelating agent DOTA depends onthe carrier molecule

The chelating agent 1,4,7,10-tetraazacyclododecane-N,N', N " ,N "'-tetraace tic acid (DOTA) is used to label monoclonal antibodies (mAbs) and peptides with Y-90. DOTA allows the generation of clinically useful stable metallic radicconjugates for the treatment of a variety of tumors, but its immunogen icity has remained controversial. In this study, we evaluated the immune re sponse to DOTA in a preclinical mouse model and in patients entered in a cl inical trial. Methods: Sera were obtained from BALB/c mice injected intrape ritoneally or subcutaneously with different doses and formulations of synge neic and xenogeneic mAbs or peptide (murine mAb Mov19 [mM19]; its chimeric version; murine V/human C ChiMov19 [cM19]; or Tyr(3)-octreotide)-DOTA conju gates. Sera from patients with neuroendocrine tumors, enrolled in a protoco l for somatostatin receptor-mediated radionuclide therapy with Y-90-DOTA-D- Phe(1)-Tyr(3)-oct-reotide (DOTATOC), were also collected before and after e ach treatment. Levels and specificity of antibody response to relevant (Mov 19, ChiMov19, or Tyr(3)-octreotide) and nonrelevant (human serum albumin) D OTA targets were tested by enzyme-linked immunosorbent assay and competitio n assays. An anti-DOTA mAb (IgG1) derived from a ChiMov19-DOTA immunized mo use was used, in a competitive radioimmunoassay, to determine the efficienc y of DOTA presentation on the different carriers. Results: Depending on the immunogenicity and dosage of the mAb, a specific anti-DOTA response was re vealed in the preclinical system. However, DOTA-peptide conjugate induced n o immune-detectable response against either chelator or carrier. DOTA was p oorly presented on small peptides, as determined using the anti-DOTA mAb. C onclusion: A humoral response against DOTA is possible, but only as a conse quence of the response elicited against the carrier. Octreotide was not imm unogenic. Thus, Y-90-DOTATOC can be considered a safe and useful tool for r eceptor-mediated radionuclide therapy of somatostatin receptor-overexpress! ng tumors.