As a leading service provider focused on drug development, BOC Sciences has been supporting customers at the forefront of drug conjugates. Immune-stimulating antibody conjugate (ISAC) is a new immunotherapy. It has both the targeting accuracy of antibody and the innate and adaptive nature of the immune system. ISAC can activate immune killing and treatment sensitivity, and has the ability to transform cold tumors into immune hot tumors by regulating immune stimulation and microenvironment. We provide Immune-stimulating antibody conjugation service to meet your unique project needs.
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ISAC consists of three main components: tumor targeting antibodies, non degradable linkers, and proprietary immune stimulants for activating the innate immune system. ISAC can activate and recruit bone marrow cells through targeting a single marker on the tumor cells to produce a new immune response. Through releasing cytokines and chemokines, attracting related immune cells and reducing the activation threshold of immune response, bone marrow cells which are activated begin the feedforward cycle. This will reprogram the tumor microenvironment, and then trigger an immune response which can be adaptive against the tumor, so as to provide a lasting response for patients.
ISAC is similar to undercover entering tumors to activate innate immunity and inform external immune cells at the same time. The following table lists the three functions and their roles of ISAC.
|Tumor antigen recognition||Drive innate immunity and specific immunity, and produce immune memory cells|
|Fcγ receptor-dependent phagocytosis||Activate dendritic cells and other antigen-presenting cells (APCs)|
|Toll-like receptors (TLR) -mediated activation||By activating CD4/CD8 T cells through TLR, cold tumors become hot tumors, which can be combined with other immune checkpoint drugs|
Table 1 Three functions and their roles of ISAC
The advantages of ISAC are mainly reflected in three aspects: action mechanism, target selection and endocytosis. The specific contents are shown in Table 2.
|Mechanism of action||ISAC is more like double antibody, which can enhance the immune response and reduce the toxicity of small molecular immune stimulants|
|Target selection||ISAC can be extended to more tumor associated antigens than traditional ADCs which using toxins|
|Endocytosis||Compared with traditional ADCs which mediate endocytosis through target antigen, ISAC mediates endocytosis through Fcγ receptor (FcγR) on the surface of immune cells and then plays a role in activating immune cells|
Table 2 Three advantages of ISAC
- Selection and screening of ligands
- Optimization of conjugation methods and linkers
- Immune-stimulating antibody conjugation
ISAC has achieved complete tumor regression and lasting anti-tumor immunity in a variety of tumor models. ISAC plays its role mainly by coupling tumor targeted monoclonal antibodies with immune agonists through non cleavable linkers. Studies have reported that APCs can be activated and induced to mature in vitro through the effect of rituximab T785-ISAC. The functional Fc fragments of TLR agonists and antibodies play vital role in activating APCs, indicating the significance of FcγR in the absorption and internalization of ISAC. The activation of APCs can be induced by ISAC through the joint action of FcγR and TLR. ISAC enhances the function of anti-tumor myeloid cells through the synergistic activity of two signal pathways. In addition, by inducing a strong pro-inflammatory environment, ISAC could accumulate activated myeloid APCs and increase the number of local cytokines and chemokines. Studies also have found the cured mice were further protected when re-implanted into the tumor, indicating that ISAC has a significant anti-refractory large tumor effect in the presence of B cells, T cells and NK cells.
Fig.1 Graphical depiction of the two-step T785-ISAC conjugation reaction.
- Different ISAC structures and batch development experience
- Various conjugation methods
- A wide range of characteristic analysis
- Data analysis, detailed report with results and discussion
- Shelley E. Ackerman; et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity [J]. Nature Cancer. 2020, 1-16.