A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND ANTI TUMOR ACTIVITY OF PF-07062119 IN PATIENTS WITH ADVANCED GASTROINTESTINAL TUMORS

A phase 1, open-label, dose escalation and expansion study of PF-07062119 in patients with selected advanced or metastatic gastrointestinal tumors

Start Date19 Nov 2019

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with CD3 x GC-C

100 Translational Medicine associated with CD3 x GC-C

0 Patents (Medical) associated with CD3 x GC-C

Literatures (Medical) associated with CD3 x GC-C

01 Dec 2021·Molecular Imaging and BiologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Pickering, Eve H ; Hussein, Amira ; Kobylarz, Keith ; Chen, Jianqing ; King, Lindsay ; Keliher, Edmund ; Rejto, Paul A ; Hardwick, James S ; Giddabasappa, Anand ; Golas, Jonathan ; Ilovich, Ohad ; Ram, Sripad ; Chen, Laigao ; Mathur, Divya ; Rosfjord, Edward ; McCarthy, Timothy J ; Narula, Jatin ; Staton, Kevin ; Schaer, David ; Root, Adam ; Wilson, Ian ; Maresca, Kevin P

AbstractPurposeA 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.

01 Jan 2021·mAbsQ2 · MEDICINE

Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors

Q2 · MEDICINE

Article

Author: Guo, Yongjing ; Katragadda, Madan ; Cunningham, Orla ; Chang, Chew Shun ; Piche-Nicholas, Nicole ; Wade, Jason ; Duan, Weili ; Liu, Yan ; Sousa, Eric ; Ma, Weijun ; Arai, Maya ; Tchistiakova, Lioudmila ; King, Lindsay ; Svenson, Kristine ; LaVallie, Edward R. ; Kelleher, Kerry ; Mathur, Divya ; Meade, Caryl ; Narula, Jatin ; Narciandi, Fernando ; Keating, Sinead E. ; Stochaj, Wayne R. ; Apgar, James R. ; Bloom, Laird ; Zhu, H. Lily ; Hendershot, Claire ; Jin, Fang ; Lawrence-Henderson, Rosemary ; Mosyak, Lidia ; Root, Adam R. ; Francis, Christopher ; McKenna, Matthew ; Betts, Alison ; Hanscom, Sara ; Wroblewska, Liliana ; Benard, Susan ; King, Amy C. ; Sapra, Puja ; Guntas, Gurkan ; D’Antona, Aaron M. ; Zhang, Yan ; Rosfjord, Edward ; Lam, Khetemcnee ; Tam, Amy ; Yang, Han ; Sheehan, Alfredo Darmanin ; Lin, Laura ; Marquette, Kimberly

We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.

01 May 2020·Clinical Cancer ResearchQ1 · MEDICINE

A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers

Q1 · MEDICINE

Article

Author: Kamperschroer, Cris ; Root, Adam R. ; Bloom, Laird ; Upeslacis, Erik ; Fernandez, Diane R. ; Bugaj-Gaweda, Bozena ; Kelleher, Kerry ; Kearney, Jessica C. ; Rosfjord, Edward ; LaVallie, Edward R. ; King, Lindsay E. ; Lucas, Justin ; Narula, Jatin ; Mathur, Divya ; Tchistiakova, Lioudmila ; Nguyen, Anhco ; Bisulco, Stephanie ; Rohde, Cynthia M. ; Sapra, Puja ; Lawrence-Henderson, Rosemary F. ; Buetow, Bernard S. ; Stevens, Chad ; Golas, Jonathan ; Tan, Xingzhi ; Guffroy, Magali ; Fang, Wei ; Yao, Johnny

AbstractPurpose:Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy.Experimental Design:PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ϵ transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti–PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque.Results:We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ϵ bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell–mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRAS- and BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti–PD-1/PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile.Conclusions:These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.

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