Bispecific Aptamer-Based Recognition-then-Conjugation Strategy for PD1/PDL1 Axis Blockade and Enhanced Immunotherapy

Area of Science:

• Immunology
• Biotechnology
• Cancer Research

Background:

• Cytotoxic T cells are crucial for antitumor immunity but can be inhibited by tumor cells expressing programmed death ligand 1 (PDL1).
• The interaction between PDL1 and its receptor programmed cell death protein 1 (PD1) acts as a brake on T-cell activity, limiting the effectiveness of immune checkpoint blockade (ICB) therapy.

Purpose of the Study:

• To develop a novel bispecific aptamer capable of simultaneously targeting PDL1 and PD1 to enhance T-cell-mediated antitumor immunity.
• To investigate a recognition-then-conjugation strategy using a labeled bispecific aptamer for improved immunotherapy efficacy.

Main Methods:

• Identification of a DNA aptamer (Ap3) that specifically binds PDL1 and inhibits PD1 binding.
• Construction of a bispecific aptamer (Ap3-7c) by integrating Ap3 with an anti-PD1 aptamer.
• Design of a DBCO-labeled bispecific aptamer (D-Ap3-7c) for covalent conjugation to PDL1 and PD1.

Main Results:

• The bispecific aptamer Ap3-7c demonstrated potential in enhancing T-cell immune responses.
• The DBCO-labeled bispecific aptamer D-Ap3-7c facilitated cell-specific recognition and covalent conjugation.
• In vivo studies confirmed that the recognition-then-conjugation strategy induced significant immunological effects against tumors.

Conclusions:

• A novel bispecific aptamer strategy targeting PDL1 and PD1 offers a promising approach for cancer immunotherapy.
• The recognition-then-conjugation method using labeled aptamers can effectively enhance antitumor immune responses.
• This work provides valuable insights for the development of advanced antitumor immunotherapies.