Abstract
CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.
Highlights
In recent years, substantial progress has been made in the development of drugs that harness the therapeutic potential of T cells for the treatment of various cancers
T cells make use of tumor targeting antibody fragments ex vivo grafted on donor T cell surfaces and (ii) recombinant CD3 bispecific protein therapeutics consisting of one binding moiety that targets CD3 on T cells while the second binding moiety is directed against a tumor-associated antigen [1,2]
The most advanced CD3 bispecific protein is Blinatumomab, a CD3/CD19 Bispecific T cell Engager (BiTE®) that received FDA approval for the treatment of refractory B-precursor acute lymphoblastic leukemia (ALL) following impressive efficacy data observed in a phase II trial [6]
Summary
Substantial progress has been made in the development of drugs that harness the therapeutic potential of T cells for the treatment of various cancers. T cells make use of tumor targeting antibody fragments ex vivo grafted on donor T cell surfaces and (ii) recombinant CD3 bispecific protein therapeutics consisting of one binding moiety that targets CD3 on T cells while the second binding moiety is directed against a tumor-associated antigen [1,2]. Focusing on the latter, bispecific proteins allow efficient engagement of T cells with tumor cells and bring them in close proximity. Due to its small size of around 50 kDa, Blinatumomab is rapidly cleared from circulation and requires a continuous intravenous (i.v.) infusion over a period of four weeks per treatment cycle [7]
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.
