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

M. E. Perico, M. Chinol, A. Nacca, E. Luison, G. Paganelli, S. Canevari

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1697-1703
Number of pages7
JournalJournal of Nuclear Medicine
Volume42
Issue number11
Publication statusPublished - 2001

Fingerprint

Octreotide
Chelating Agents
Humoral Immunity
Somatostatin Receptors
Peptides
Radioisotopes
Monoclonal Antibodies
Heterophile Antibodies
Neuroendocrine Tumors
Therapeutics
Serum
Serum Albumin
Antibody Formation
Radioimmunoassay
Neoplasms
Immunoglobulin G
Enzyme-Linked Immunosorbent Assay
Clinical Trials

Keywords

  • Antimacrocyclic antibodies
  • DOTA
  • Immunogenicity
  • Receptor-mediated radionuclide therapy

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule. / Perico, M. E.; Chinol, M.; Nacca, A.; Luison, E.; Paganelli, G.; Canevari, S.

In: Journal of Nuclear Medicine, Vol. 42, No. 11, 2001, p. 1697-1703.

Research output: Contribution to journalArticle

Perico, M. E. ; Chinol, M. ; Nacca, A. ; Luison, E. ; Paganelli, G. ; Canevari, S. / The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule. In: Journal of Nuclear Medicine. 2001 ; Vol. 42, No. 11. pp. 1697-1703.
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abstract = "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.",
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T1 - The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule

AU - Perico, M. E.

AU - Chinol, M.

AU - Nacca, A.

AU - Luison, E.

AU - Paganelli, G.

AU - Canevari, S.

PY - 2001

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N2 - 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.

AB - 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.

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