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IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab—pharmacokinetic modeling to optimize therapeutic index

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Abstract

Purpose

Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases.

Methods

Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound “harmful” antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)].

Results

The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48–1.40 mg or 881–2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%.

Conclusion

The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation.

Clinical trial registration

ClinicalTrials.gov, NCT00089245.

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Availability of data and material

Data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

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Acknowledgments

We thank Anita Tsen-hui Louie of Vanderbilt University and Ronald Blasberg of Memorial Sloan Kettering Cancer Center for their critical review and revisions of the manuscript.

Funding

This was supported in part by the NCI Cancer Center Support Grant P30 CA008748, Enid A. Haupt Endowed Chair (NKC), and the Robert Steel Foundation (NKC).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Rahul S. Yerrabelli, Kim Kramer, Hongfen Guo & Nai-Kong V. Cheung

  2. Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, 807 South Wright Street, Suite 320, Champaign, IL, 61820, USA

    Rahul S. Yerrabelli

  3. Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY, 11794, USA

    Ping He

  4. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Edward K. Fung, Pat B. Zanzonico & John L. Humm

  5. Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA

    Edward K. Fung

  6. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Neeta Pandit-Taskar & Steven M. Larson

Authors
  1. Rahul S. Yerrabelli
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  2. Ping He
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Corresponding author

Correspondence to Nai-Kong V. Cheung.

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Conflict of interest

NKC reports receiving commercial research grants from Y-mabs Therapeutics and Abpro-Labs Inc.; holding ownership interest/equity in Y-Mabs Therapeutics Inc., holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. NKC is the inventor and owner of issued patents licensed by MSK to Ymabs Therapeutics, Biotec Pharmacon, and Abpro-labs. Naxitamab and omburtamab were licensed by MSK to Y-mabs Therapeutics. Both MSK and NKC have financial interest in Y-mabs. NKC is an advisory board member for Abpro-Labs and Eureka Therapeutics.

Ethical approval

Prior to enrolling patients, the human subjects research described in this article was approved by the Institutional Review Board of Memorial Sloan Kettering Cancer Center and listed on clinicaltrials.gov (NCT00089245). All patients taking part in the study or their legal guardian provided informed consent to participate in the clinical trial. This study was performed in line with the principles of the Declaration of Helsinki.

Code availability

Data and computational parameters used in MATLAB are supplied as supplement to this manuscript. The model and ready-to-run code to run it have been made available in reference [15].

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Yerrabelli, R.S., He, P., Fung, E.K. et al. IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab—pharmacokinetic modeling to optimize therapeutic index. Eur J Nucl Med Mol Imaging 48, 1166–1177 (2021). https://doi.org/10.1007/s00259-020-05050-z

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