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Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

ABSTRACT: Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

PROVIDER: PRJNA762698 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15862400_1.fastq.gz	Fastqsanger.gz
	SRR15862400_2.fastq.gz	Fastqsanger.gz
	SRR15862501_1.fastq.gz	Fastqsanger.gz
	SRR15862501_2.fastq.gz	Fastqsanger.gz
	SRR15862402_1.fastq.gz	Fastqsanger.gz

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Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

Project description:Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activating the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been significantly restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type-1 dendritic cells are essential for triggering antitumor immunity but not toxicity by CD40 agonists, while macrophages, platelets, and monocytes lead to the toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody, while triggering potent anti-tumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.

2021-12-12 | GSE184009 | GEO

PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy

Project description:Most cancers are cold tumors characterized by a lack of effector T cells and hence unresponsive to immune checkpoint blockades, highlighting the importance of repairing the failed T cell priming in cancer immunotherapy. CD40 agonists are efficient in eliciting T cell responses and effective in converting cold tumors into hot, their clinical application, however, is limited by the very narrow window between the effective and toxic dosages. Here, we sought to reduce the effective dosage of CD40 agonists by combination therapy. We identified a CD19+CD24hiCD38lowIgDlow/- regulatory B cell (Breg) subset that is increased in tumor-bearing mice and cancer patients, and discovered that PPARδ is highly expressed in these tumor-associated Bregs and required for their proliferation and function. Inhibition of PPARδ acted synergistically with agonist anti-CD40 to enhance antitumor immunity without increasing toxicity in murine melanoma and bladder carcinoma models. Combination therapy with PPARδ inhibitor could reduce anti-CD40 dosage by over 60% to a well-tolerated level with improved or at least not compromised antitumor effects, providing a potential strategy for safely using CD40 agonists in cancer treatment. PPARδ also offers a new target for selectively blocking Breg activity while sparing immunostimulatory B cells that are known to aid antitumor immunotherapy.

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The immune checkpoint regulator CD40 potentiates myocardial inflammation

Project description:Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leverage genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2+ macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

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Cd40

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Project description:Efficacy of CD40 agonists is mediated by distinct cDC subsets and subverted by suppressive macrophages

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Project description:Macaca mulatta CD40, CD40 molecule [Source:VGNC Symbol;Acc:VGNC:70703], is expressed in 2 baseline experiment(s);

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