A bioengineered antibody conjugate reshape dendritic cell viability for immune-tolerance modulation

Immune tolerance leads to the suppression of effector cell functions and facilitates persistent chronic viral infections and tumor progression. Activating specific pattern recognition receptors on antigen-presenting cells represents a potent strategy for enhancing the host’s immune defense and regulating the immune response, but efficiently delivering receptor agonists has always been a formidable challenge. In this work, we developed an immune-stimulated antibody conjugate, HB290-DA-IDMQ, using an innovative bioengineering strategy to deliver TLR7/8 agonists to dendritic cells (DCs) via a DEC-205-targeting antibody with reduced Fc function. HB290-DA-IMDQ enhances the activation of targeted DCs, thereby achieving efficient maturation, antigen presentation by DCs and the stimulation of specific immune responses, while addressing the challenge of excessive cytokine release caused by the potent activity of traditional agonists. This therapeutic strategy has shown superior efficacy over the combination of free agonist and DEC-205-targeting antibodies in mouse models of immune-tolerant chronic hepatitis B virus infection and MC38 tumor-bearing mice, demonstrating a robust immunomodulatory effect. This advancement underscores the important role of our bioengineered antibody conjugate in reshaping the functionality of DCs in immune tolerance regulation, providing a new perspective for the management of chronic viral infections and malignancies.