Preclinical Evaluation of 89 Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy.

Autor: Maresca KP; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA. kevin.maresca@pfizer.com., Chen J; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Mathur D; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.; Regneron Pharmaceuticals, Tarrytown, NY, USA., Giddabasappa A; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Root A; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.; Generate Biomedicines, Inc, Cambridge, MA, USA., Narula J; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., King L; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Schaer D; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Golas J; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.; Regneron Pharmaceuticals, Tarrytown, NY, USA., Kobylarz K; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Rosfjord E; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.; Black Diamond Therapeutics, New York, NY, USA., Keliher E; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Chen L; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Ram S; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Pickering EH; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Hardwick JS; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Rejto PA; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA., Hussein A; Invicro, A Konica Minolta Company, New Haven, USA., Ilovich O; Invicro, A Konica Minolta Company, New Haven, USA., Staton K; Evergreen Theragnostics, Jersey City, NJ, USA.; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wilson I; ImaginAb Inc., Inglewood, CA, USA., McCarthy TJ; Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.
Jazyk: angličtina
Zdroj: Molecular imaging and biology [Mol Imaging Biol] 2021 Dec; Vol. 23 (6), pp. 941-951. Date of Electronic Publication: 2021 Jun 18.
DOI: 10.1007/s11307-021-01621-0
Abstrakt: Purpose: A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89 Zr-Df-IAB22M2C ( 89 Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89 Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining.
Procedures: NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89 Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89 Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells.
Results: The results demonstrated substantial mean uptake of 89 Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119.
Conclusion: Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89 Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.
(© 2021. The Author(s).)
Databáze: MEDLINE
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