Abstract
A promising strategy in cancer immunotherapy is the employment of a bispecific agent that can bind with both tumor markers and immunocytes for recruitment of lymphocytes to tumor sites and enhancement of anticancer immune reactions. Mucin1 (MUC1) is a tumor marker overexpressed in almost all adenocarcinomas, making it a potentially important therapeutic target. CD16 is expressed in several types of immunocytes, including NK cells, γδ-T cells, monocytes, and macrophages. In this study, we constructed the first bispecific aptamer (BBiApt) targeting both MUC1 and CD16. This aptamer consisted of two MUC1 aptamers and two CD16 aptamers linked together by three 60 nt DNA spacers. Compared with monovalent MUC1 or CD16 aptamers, BBiApt showed more potent avidity to both MUC1-positive tumor cells and CD16-positive immunocytes. Competition experiments indicated that BBiApt and monovalent aptamers bound to the same sites on the target cells. Moreover, BBiApt recruited more CD16-positive immunocytes around MUC1-positive tumor cells and enhanced the immune cytotoxicity against the tumor cells in vitro. The results suggest that, apart from bispecific antibodies, bispecific aptamers may also potentially serve as a novel strategy for targeted enhancement of antitumor immune reactions against MUC1-expressing malignancies.
Highlights
Cancer is one of the leading causes of death in the 21st century
A selected bispecific made of MUC1 and the CD16 aptamer wasin selected by Achim
A bispecific aptamer made of MUC1 and
Summary
Cancer is one of the leading causes of death in the 21st century. With the growth of the aging population worldwide, the burden of cancer continues to increase due to growth of incidence [1,2]. Traditional cancer therapies include surgery, chemotherapy, and radiotherapy. Cancer immunotherapy became mainstream treatment in the past decade [3]. The major progresses in cancer immunotherapy are highlighted by chimeric antigen receptor T (CAR-T) cell therapy and immune checkpoint blockade (ICB). CAR-T therapy achieved remarkable success in hematologic malignancy. CD19-directed CAR-T therapy was efficacious in treating relapsed and refractory acute lymphoblastic leukemia (ALL) with very high response rates [4]. CAR-T therapy requires extraction of each patient’s autologous T-cells followed by lentivirus treatment to generate tumor-antigen specific T-cells. CAR-T therapy is extremely expensive due to the costs of T-cells culturing, processing, storage, and transportation. ICB, such as PD-1/PD-L1 antibodies, can stimulate the patient’s immune system and unleash antitumor immune activities
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