Abstract

To exploit the biological and pharmacological properties of immunoglobulin constant domain Fc fragment and increase the killing efficacy of T cells, a single chain variable fragment specific to CD3 was fused with Fcab (Fc antigen binding), a mutant Fc fragment with specificity against Human epidermal growth factor receptor 2 (HER2) developed by F-star. The bispecific fusion named as FcabCD3 was expressed by transient transfection in HEK-293T cells and purified by affinity chromatography. Specific cytolytic activity of retargeted T cells to kill HER2 positive SKBR3 cell line was evaluated in vitro. FcabCD3 was able to retarget T cells to kill both Herceptin insensitive Colo205-luc cell line and HER2 low expression MDA-MB-231-luc cell line. Furthermore, FcabCD3 was effective in eliminating the Colo205 tumor established on BALB/c nu/nu mice.

Highlights

  • Antibodies have emerged as one of effective therapeutics against a plethora of diseases including cancer and autoimmune disorders [1,2]

  • Human epidermal growth factor receptor 2 (HER2) is an attractive target for breast cancer immunotherapy

  • It is widely expressed on many human tumors including ovarian, bladder, salivary gland, endometrial, pancreatic and non-small-cell lung cancer (NSCLC) [21]

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Summary

Introduction

Antibodies have emerged as one of effective therapeutics against a plethora of diseases including cancer and autoimmune disorders [1,2]. To expand the application of antibody-based therapeutics, antibodies have been further designed to bind simultaneously to two different antigens. Such antibodies with bispecific or multispecific targeting abilities have offered wide applications in both diagnostics and therapeutics. The majority of bispecific antibodies in the clinic include: 1, Simultaneous targeting of multiple receptors; 2, Delivery of payloads, toxins and other functional proteins [4,5]; 3, Recruitment of effector cells through one of FcγR receptors or CD3 receptor to tumors with a tumor associated marker [6]. The most successful bispecific antibodies (bsAb) belong to those that recruit cytotoxic T cells to the site of tumor cells, for instance, Catumaxomab, an anti-

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