Over the past 15 years, immunotherapy represented by checkpoint inhibitors has brought about dramatic changes in cancer treatment, but the effectiveness of this type of therapy is still limited. For example, most patients treated with PD-1/L1 inhibitors have not achieved complete remission, and only a few patients have sustained tumor regression after treatment.
Toll-like receptor (TLR) agonists can activate antigen presenting cells (APC) and enhance the immunity of T cells to tumor neoantigens. Combined with this type of innate immune agonist, the anti-tumor activity of immune checkpoint inhibitors can be enhanced. However, the systemic administration of TLR agonists often causes toxic reactions. Although intratumoral injection can improve the drug tolerance, it is also limited by some factors such as tumor size in practice.
In a new study published in Nature Cancer on December 7, researchers from Bolt Biotherapeutics and Stanford University School of Medicine have developed an immune-stimulating antibody conjugates (ISAC). It combines the accuracy of antibody targeting tumors with the killing potential of the innate and adaptive immune system into a single drug, achieving complete tumor regression and durable anti-tumor immunity in multiple tumor models.
ISAC is composed of a tumor-targeted monoclonal antibody coupled to an immune agonist through a non-cleavable linker. In this study, the researchers designed to combine rituximab with a TLR7/8 agonist (T785) through linker to generate T785-ISAC, and the immunostimulatory potential of T785-ISAC is not limited to rituximab.
Rituximab T785-ISAC (Source: Nature Cancer)
In vitro experiments, rituximab TLR7/8 ISAC can activate antigen presenting cells (APC) and induce their maturation. The activation of APC depends on TLR agonists and functional Fc fragments of antibodies. It indicates the importance of Fc receptors (FcγR ) in the absorption and internalization of ISAC.
ISAC requires Fc effector function to mediate the activation of myeloid APC (Source: Nature Cancer)
ISAC induces APC activation through the combined action of FcγR and TLR, and the synergistic activity of the two signaling pathways provides ISAC with the ability to enhance the function of anti-tumor myeloid cells.
ISAC: One antibody, two attacks (Source: Nature Cancer)
In order to determine whether the covalent linkage of T785 and monoclonal antibody would amplify anti-tumor immunity in vivo, the researchers found that trastuzumab T785-ISAC systemic administration strongly controlled tumor growth in the HER2-expressing xenograft model of trastuzumab resistance.
ISAC induces strong anti-tumor immunity in tumor xenograft models against trastuzumab (Source: Nature Cancer)
In addition, ISAC induces a strong pro-inflammatory environment, which leads to the accumulation of activated myeloid APCs and increases in local cytokines and chemokines.
The researchers then evaluated the efficacy of ISAC against refractory large tumors (about 500mm3) in the presence of B cells, T cells and NK cells. Mice expressing rHER2 were cured after receiving trastuzumab T785-ISAC therapy targeting HER2, the tumors completely resolved, and the cured mice were further protected when the tumor was implanted again.
ISAC has powerful anti-tumor effects in homologous mouse tumor models (Source: Nature Cancer)
The researchers also tested CL264-ISAC, which is a TLR7-specific agonist. The results show that CL264-ISAC is more effective than T785-ISAC in inducing the activation and anti-tumor activity of myeloid APC in vivo, which confirms that the efficacy of TLR agonists can affect the efficacy of ISAC.
Source: Nature Cancer
However, CL264-ISAC caused systemic cytokine secretion and transient weight loss, suggesting that there may be treatment-related toxicity. Another possible limitation of ISAC is the production of anti-drug antibodies. ISAC may promote the production of anti-drug antibodies and affect the efficacy of drugs.
In general, the new ISAC therapy has strong preclinical anti-tumor activity, and these research results provide a strong basis for the clinical development of ISAC. It is reported that the ISAC drug BDC-1001 introduced in this study is undergoing clinical phase I/II studies in patients with HER2-expressing tumors.
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 Ackerman, S. E., Pearson, C. I., Gregorio, J. D. et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer (2020)
Demaria, O., Vivier, E. ISACs take a Toll on tumors. Nature Cancer (2020)
Data Published in Nature Cancer Highlight Preclinical Proof of Concept of Bolt Biotherapeutics' Boltbody ISAC Platform