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PET-based compartmental modeling of 124I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the “best-fit” parameters and model-derived quantities for optimizing biodistribution of intravenously injected 124I-labeled antitumor antibodies.

Methods

As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as “A33”) were performed in 11 colorectal cancer patients. Serial whole-body PET scans of 124I-labeled A33 and blood samples were acquired and the resulting tissue time–activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code.

Results

Excellent agreement was observed between fitted and measured parameters of tumor uptake, “off-target” uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy.

Conclusion

This approach should be generally applicable to antibody–antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient’s resulting “best-fit” nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived.

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Notes

  1. The association rate constant (k a) is the fractional rate of binding of the antibody to the antigen per unit concentration of unbound antigen, expressed, for example, in the unit of /M/h.

  2. The model parameter k(i,j) (sometimes known as an “exchange rate”) is the fractional rate of transport of the A33 antibody from compartment j to compartment i, expressed, for example, in the unit of /h.

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Acknowledgments

We thank research assistants Christina Hong, Ernest Flatts, and Christine Pierre for their administrative support, Anabella Lindo, RN, and Susan Reyes, RN, for patient care, radiochemist Jing Qiao for radioiodination of the antibody, and the technologists of the Nuclear Medicine Service for their assistance in PET and PET/CT imaging of the patients.

Compliance with ethical standards

ᅟ

Conflicts of Interest

None.

Statement of human rights

All procedures performed in studies involving human participants were approved by the Institutional Review Board (IRB) of Memorial Sloan Kettering Cancer Center and were in accordance with the ethical standards of our institution and with the principles of the 1964 Declaration of Helsinki and its later amendments.

Statement on the welfare of animals

This article does not describe any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Funding

This study was supported by the Ludwig Center for Cancer Immunotherapy and National Institutes of Health (NIH) grant numbers P50 CA 86438-11 and PO1 CA 33049.

Author information

Author notes

  1. Peter Smith-Jones

    Present address: Departments of Psychiatry and Radiology, Stony Brook School of Medicine, Stony Brook, NY, USA

  2. Yuman Fong

    Present address: Department of Surgery, City of Hope, Duarte, CA, USA

Authors and Affiliations

  1. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Pat Zanzonico, Joseph A. O’Donoghue & John L. Humm

  2. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jorge A. Carrasquillo, Neeta Pandit-Taskar, Peter Smith-Jones, Shutian Ruan & Steven M. Larson

  3. Columbia University Medical Center, New York, NY, USA

    Chaitanya Divgi

  4. Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia

    Andrew M. Scott

  5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nancy E. Kemeny, Douglas Wong & David Scheinberg

  6. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yuman Fong

  7. Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Gerd Ritter, Achem Jungbluth & Lloyd J. Old

Authors
  1. Pat Zanzonico
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  2. Jorge A. Carrasquillo
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Corresponding author

Correspondence to Pat Zanzonico.

Additional information

Douglas Wong, and Lloyd J. Old were deceased.

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Zanzonico, P., Carrasquillo, J.A., Pandit-Taskar, N. et al. PET-based compartmental modeling of 124I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer. Eur J Nucl Med Mol Imaging 42, 1700–1706 (2015). https://doi.org/10.1007/s00259-015-3061-2

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  • DOI: https://doi.org/10.1007/s00259-015-3061-2

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