Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

Ackerman, Shelley E.; Pearson, Cecelia I.; Gregorio, Joshua; González, Joseph C.; Kenkel, Justin A.; Hartmann, Felix J.; Luo, Angela; Ho, Po Y.; Leblanc, Heidi; Blum, Lisa K.; Kimmey, Samuel C.; Luo, Andrew; Nguyen, Murray L.; Paik, Jason C.; Sheu, Lauren Y.; Ackerman, Benjamin; Lee, Arthur; Li, Hai; Melrose, Jennifer; Laura, Richard; Ramani, Vishnu C.; Henning, Karla A.; Jackson, David Y.; Safina, Brian S.; Yonehiro, Grant; Devens, Bruce H.; Carmi, Yaron; Chapin, Steven J.; Bendall, Sean C.; Kowanetz, Marcin; Dornan, David; Engleman, Edgar G.; Alonso, Michael N.

doi:10.1038/s43018-020-00136-x

Cited by 118 publications

(65 citation statements)

References 64 publications

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“…With the idea to combine the precision of a therapeutic antibody with the stimulation of innate immunity cells into a single agent, Ackerman et al recently reported the design of BDC-1001, an immune-stimulating antibody conjugate, engaging TLR7 and TLR8 and conjugated to a tumour-targeting antibody against HER2. In mice, systemic administration of this immune-stimulating antibody conjugate successfully reduced tumour growth and stimulated an antitumour immune response mediated by macrophages and other antigen-presenting cells, without eliciting inflammation 162 . SBT6050 is a TLR8 agonist conjugated to a HER2-directed antibody.…”

Section: Macrophage Activationmentioning

confidence: 99%

Macrophages as tools and targets in cancer therapy

Mantovani

Allavena

Marchesi

et al. 2022

Nat Rev Drug Discov

891

508

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Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium.

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Section: Macrophage Activationmentioning

confidence: 99%

Macrophages as tools and targets in cancer therapy

Mantovani

Allavena

Marchesi

et al. 2022

Nat Rev Drug Discov

891

508

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“…This suggests that combination treatment could be beneficial in a subgroup of patients. Toxicities of the TLR agonist treatment due to widespread immune cell activation can be overcome by local, intra- or peritumoral injections [ 46 , 47 , 48 ], or by conjugation of TLR agonists to antibodies [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

NK Cell-Dependent Antibody-Mediated Immunotherapy Is Improved In Vitro and In Vivo When Combined with Agonists for Toll-like Receptor 2 in Head and Neck Cancer Models

Gruijs

Ganzevles

Walsum

et al. 2021

IJMS

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The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression.

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“…Antibody conjugation has also been explored to enable tumor-targeted IMD delivery. BDC-1001, a TLR7/8 agonist conjugated to the anti-HER2 IgG 1 monoclonal antibody trastuzumab, is currently in phase I trials in combination with pembrolizumab [ 155 , 156 ]. In the same vein, SBT-6050 is an antibody conjugated TLR8-specific agonist that is advancing toward the clinic based on strong preclinical results.…”

Section: Preclinical and Clinical Development Of Tlr7/8 Agonistsmentioning

confidence: 99%