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Mouse Models of Cancer Study

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Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor

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Exploring the Interplay Between Radioimmunoconjugates and Fcγ Receptors in Genetically Engineered Mouse Models of

Cindy Rodriguez^1,2,3, Samantha M Sarrett^1,2,4, Joni Sebastiano^1,2,4

¹Department of Chemistry, Hunter College, City University of New York, New York 10021, New York, United States.

ACS Pharmacology & Translational Science

|November 14, 2024

Summary

The presence of endogenous IgG influences how Fc gamma receptors (FcγR) affect radiolabeled antibody pharmacokinetics in mice. This finding is crucial for developing effective cancer immunotherapeutics.

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Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies

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Published on: May 22, 2020

Area of Science:

Immunology
Radiopharmaceutical Science
Oncology

Background:

Fc gamma receptors (FcγR) mediate immunoglobulin G (IgG) interactions with immune cells, impacting immunotherapeutics.
The role of FcγR in the in vivo behavior of radiolabeled antibodies remains poorly understood, especially in cancer models.

Purpose of the Study:

To investigate the impact of FcγR binding on the pharmacokinetics of 89Zr-labeled radioimmunoconjugates targeting CA19-9.
To compare the in vivo performance of wild-type and aglycosylated 89Zr-labeled antibodies in various mouse models.

Main Methods:

Synthesis and characterization of 89Zr-labeled wild-type (DFO-5B1) and aglycosylated (DFO-N297A5B1) CA19-9-targeting antibodies.
Evaluation of antibody binding affinity to CA19-9 and FcγR.
In vivo positron emission tomography imaging and biodistribution studies in immunocompromised NSG, immunocompetent C57BL/6, and FcγR-humanized C57BL/6 mice bearing cancer xenografts.

Main Results:

The aglycosylated immunoconjugate showed similar CA19-9 binding but reduced FcγR affinity compared to the wild-type.
Pharmacokinetic differences were observed in tumor-bearing NSG mice but not in immunocompetent or FcγR-humanized mice.
Differences in pharmacokinetics correlated with the presence or absence of endogenous IgG, which occupies FcγR in immunocompetent models.

Conclusions:

Endogenous IgG levels significantly influence the interaction between radiolabeled antibodies and FcγR, affecting their pharmacokinetic profiles in vivo.
Understanding FcγR interplay with radiolabeled antibodies is critical for preclinical assessment of radioimmunoconjugates.
These findings have implications for the design and optimization of antibody-based radiotherapeutics and imaging agents.