Abstract
PurposeA 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 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-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.ProceduresNOD 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 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-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.ResultsThe results demonstrated substantial mean uptake of 89Zr-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.ConclusionImmune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.
Highlights
In the expanding field of immuno-oncology (IO), there is a growing need for earlier and more accurate in vivo molecular markers that can measure immune responses to an increasing number of IO therapies (IOT)
We evaluated the uptake of 89Zr-DfIAB22M2C in a colorectal cancer (CRC) LS1034 tumor-bearing mice inoculated with activated T cells, which were subsequently treated with either GUCY2C-CD3 bispecific antibody PF-07062119 (a novel T cell engaging bispecific antibody treatment for GUCY2C expressed tumors (Figure S1)) or a non-targetedCD3 bispecific control PF-07069699 as previously studied [14, 18], using Positron emission tomography (PET)/CT imaging and gamma counting
We demonstrated the initial steps to qualify the ability of the CD8 Mb PET tracer 89Zr-Df-IAB22M2C to quantify the recruitment of human CD8+ T cells to tumors following treatment with the GUCY2C-CD3 BsAb PF07062119 with high sensitivity and robustness
Summary
In the expanding field of immuno-oncology (IO), there is a growing need for earlier and more accurate in vivo molecular markers that can measure immune responses to an increasing number of IO therapies (IOT). Positron emission tomography (PET) is a well-established non-invasive imaging technique that has the sensitivity to detect changes in biological processes at the molecular level and has expanded to include ImmunoPET, which employs antibody-based radiotracers to image tumors based on expression of tumor-associated antigens [4,5,6]. PET imaging is a quantifiable and clinically translatable technique, most widely used in clinical oncology for detection of tumors and staging of disease [7]. PET imaging can impact treatment decisions in IO through the ability to perform whole-body imaging, potentially directing biopsy, and identifying lesions that are either responding or not responding to therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
