CD80-Fc fusion protein as a potential cancer immunotherapy strategy
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PROVIDER: S-EPMC10791041 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Immune checkpoint inhibitors (ICIs) have significantly advanced the field of cancer immunotherapy. However, clinical data has shown that many patients have a low response rate or even resistance to immune checkpoint inhibitor alone. The underlying reasons for its poor efficacy include the deficiency of immune infiltration and effective CD28/CD80 costimulatory signal in tumor. Discoidin domain receptor 1 (DDR1) has been reported to be negatively related to immune cell infiltration in tumors. Herein, we constructed a soluble fusion protein using CD80, the natural ligand of CD28, in combination with DDR1 inhibitor. Our results demonstrated that CD80-Fc effectively activated T cells and inhibited tumor growth in vivo, even in tumors with poor efficacy of ICIs. Importantly, CD80-Fc fusion protein had a milder affinity against the targets which suggested a potential higher safety than CD28 agonists. Further, in order to promote tumor immune infiltration, we attempted to combine CD80-Fc fusion protein with DDR1 inhibitor for treatment. Our results indicated that using CD80-Fc fusion protein along with DDR1 inhibitor significantly promoted T cell infiltration in tumor microenvironment and more strongly inhibited tumor growth. Therefore, the combination use of CD80 fusion protein and DDR1 inhibitor could become an effective tumor immunotherapy strategy, potentially benefiting a larger number of patients. KEY POINTS: • We successfully constructed, expressed, and purified the recombinant CD80-Fc fusion protein • We demonstrated that CD80-Fc fusion protein has good safety and anti-tumor activity • We demonstrated that using CD80-Fc fusion protein along with DDR1 inhibitor can significantly promote immune infiltration of T cells in tumor microenvironment and more strongly inhibit tumor growth.
| S-EPMC11805834 | biostudies-literature
Project description:BackgroundThe ubiquitously expressed transmembrane protein, Herpesvirus Entry Mediator (HVEM), functions as a molecular switch, capable of both activating and inhibiting the immune response depending on its interacting ligands. HVEM-Fc is a novel recombinant fusion protein with the potential to eradicate tumor cells.MethodsThe anti-tumor efficacy of HVEM-Fc was evaluated in C57BL/6 mice-bearing lung cancer models: a syngeneic model and an orthotopic model of mouse lung cancer. Additionally, patient-derived organoids were employed in conjunction with T cell co-culture systems. To investigate the underlying mechanisms, a comprehensive array of techniques was utilized, including single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and flow cytometry. Furthermore, the anti-tumor effects of HVEM-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed. Finally, mouse immune cell depletion antibodies were used to elucidate the underlying mechanisms of action.ResultsIn vivo, 1 mg/kg HVEM-Fc demonstrated effective inhibition of tumor growth and metastasis in C57BL/6 mice bearing lung cancer model and a KP orthotopic model of mouse lung cancer. Multi-omics analysis showed that HVEM-Fc induced an immune-stimulatory microenvironment. Notably, the combination of HVEM-Fc with a PD-1 inhibitor demonstrated the most potent inhibition of tumor cell growth. In vitro, HVEM-Fc was validated to eradicate tumor cells through the activation of T cells in both non-small cell lung cancer (NSCLC) organoids and T cell co-culture models.ConclusionsOur data demonstrate that HVEM-Fc exerts a strong signal that augments and prolongs T-cell activity in both murine models and human NSCLC organoid models. Moreover, the combination of HVEM-Fc with a PD-1 inhibitor yields the most effective anti-tumor outcomes.
| S-EPMC11841141 | biostudies-literature
Project description:The clinical application of immunotherapy is the milestone of cancer treatment. However, some patients have bad reaction. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple cancer cells and is associated with poor prognosis. It is the key enzyme of prostaglandin E2 (PGE2) that has been proved to promote the development, proliferation and metastasis of tumor cells. Recent studies further find the PGE2 in tumor microenvironment (TME) actively triggers tumor immune evasion via many ways, leading to poor response of immunotherapy. COX-2 inhibitor is suggested to restrain the immunosuppression of PGE2 and may enhance or reverse the response of immune checkpoint inhibitors (ICIs). This review provides insight into the mechanism of COX-2/PGE2 signal in immunosuppressive TME and summarizes the clinical application and trials in cancer treatment.
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Project description:T cell responses are fine-tuned by co-stimulatory and co-inhibitory molecules. Among the T cell regulators, the B7 family members are of central importance. The recent success in targeting the B7 family molecules for the treatment of immune-related diseases has attracted intense interest in identifying additional B7-related molecules. In this study, we describe CD300c as a novel T cell co-inhibitory molecule that shares significant sequence homology with existing B7 family members. CD300c protein is expressed on professional antigen-presenting cells (APC), including B cells, monocytes, macrophages, and dendritic cells (DCs). The putative CD300c counter-receptor is expressed on CD4 and CD8 T cells, and the expression levels are upregulated upon activation. Soluble human and mouse CD300c-Fc fusion proteins significantly inhibit the proliferation, activation, and cytokine production by CD4 and CD8 T cells in vitro. Administration of CD300c-Fc protein attenuates graft-vs.-host disease (GVHD) in mice. Our results suggest that therapeutic interaction with the CD300c inhibitory pathway may represent a new strategy to modulate T cell-mediated immunity for the treatment of GVHD and autoimmune disease.
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Project description:Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.
| S-EPMC8225389 | biostudies-literature
Project description:The CTLA4-Ig fusion proteins abatacept and belatacept are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplant, respectively. Given that both biologics are typically administered chronically by infusion, a need exists for a next-generation CTLA4-Ig with more convenient dosing. We used structure-based protein engineering to optimize the affinity of existing CTLA4-Ig therapeutics for the ligands CD80 and CD86, and for the neonatal Fc receptor, FcRn. From a rationally designed library, we identified four substitutions that enhanced binding to human CD80 and CD86. Coupled with two IgG1 Fc substitutions that enhanced binding to human FcRn, these changes comprise the novel CTLA4-Ig fusion protein, XPro9523. Compared with abatacept, XPro9523 demonstrated 5.9-fold, 23-fold, and 12-fold increased binding to CD80, CD86, and FcRn, respectively; compared with belatacept, CD80, CD86, and FcRn binding increased 1.5-fold, 7.7-fold, and 11-fold, respectively. XPro9523 and belatacept suppressed human T cell proliferation and IL-2 production more potently than abatacept. XPro9523 also suppressed inflammation in the mouse collagen-induced arthritis model. In cynomolgus monkeys, XPro9523 saturated CD80 and CD86 more effectively than abatacept and belatacept, potently inhibited IgM and IgG immunization responses, and demonstrated longer half-life. Pharmacokinetic modeling of its increased potency and persistence suggests that, in humans, XPro9523 may demonstrate superior efficacy and dosing convenience compared with abatacept and belatacept.
| S-EPMC4169032 | biostudies-literature
Project description:Oncolytic viruses armed with therapeutic transgenes of interest show great potential in cancer immunotherapy. Here, a novel oncolytic adenovirus carrying a signal regulatory protein-α (SIRPα)-IgG1 Fc fusion gene (termed SG635-SF) was constructed, which could block the CD47 'don't eat me' signal of cancer cells. A strong promoter sequence (CCAU) was chosen to control the expression of the SF fusion protein, and a 5/35 chimeric fiber was utilized to enhance the efficiency of infection. As a result, SG635-SF was found to specifically proliferate in hTERT-positive cancer cells and largely increased the abundance of the SF gene. The SF fusion protein was effectively detected, and CD47 was successfully blocked in SK-OV3 and HO8910 ovarian cancer cells expressing high levels of CD47. Although the ability to induce cell cycle arrest and cell death was comparable to that of the control empty SG635 oncolytic adenovirus in vitro, the antitumor effect of SG635-SF was significantly superior to that of SG635 in vivo. Furthermore, CD47 was largely blocked and macrophage infiltration distinctly increased in xenograft tissues of SK-OV3 cells but not in those of CD47-negative HepG2 cells, indicating that the enhanced antitumor effect of SG635-SF was CD47-dependent. Collectively, these findings highlight a potent antitumor effect of SG635-SF in the treatment of CD47-positive cancers.
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Project description:The main complication of replacement therapy with factor in hemophilia A (HemA) is the formation of inhibitors (neutralizing anti-factor VIII [FVIII] antibodies) in ∼30% of severe HemA patients. Because these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them is of top priority in disease management. The extended half-life recombinant FVIII Fc fusion protein (rFVIIIFc) is an approved therapy for HemA patients. In addition, it has been reported that rFVIIIFc may induce tolerance to FVIII more readily than FVIII alone in HemA patients that have developed inhibitors. Given that the immunoglobulin G1 Fc region has the potential to interact with immune cells expressing Fc receptors (FcRs) and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both FcRs and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-FcR interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.
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Project description:Computational design of novel proteins with well-defined functions is an ongoing topic in computational biology. In this work, we generated and optimized a new synthetic fusion protein using an evolutionary approach. The optimization was guided by directed evolution based on hydrophobicity scores, molecular weight, and secondary structure predictions. Several methods were used to refine the models built from the resulting sequences. We have successfully combined two unrelated naturally occurring binding sites, the immunoglobin Fc-binding site of the Z domain and the DNA-binding motif of MyoD bHLH, into a novel stable protein.
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Project description:In this study, we assess an alternative Fc-fusion protein purification method that does not rely on chromatographic media or ligands. Recombinant human acetylcholinesterase, fused to the Fc domain of human IgG1 (henceforth, AChE-Fc), was purified with precipitated aromatic complexes composed of the bathophenanthroline (henceforth, batho) chelator with either Zn2+ or Cu2+ ions (i.e., [(batho)3:Zn2+] or [(batho)2:Cu2+]) in the presence of polyethylene glycol 6000 (PEG-6000). In a three-step purification process conducted at pH 7, AChE-Fc was captured by the aromatic complexes (Step 1); unbound or weakly bound protein impurities were removed with 20 mM NaCl (Step 2); and AChE-Fc was then extracted at pH 7 (Step 3) using 100 mM Na citrate buffer in 250 mM NaCl. Purified AChE-Fc was not aggregated (as determined by dynamic light scattering (DLS) and Native PAGE). However, full enzymatic activity was only preserved with the [(batho)3:Zn2+] complex. Interaction between AChE-Fc and [(batho)3:Zn2+] led to ~83-88% overall protein yield. Thirty-fold process upscaling by volume required only proportional increase in the amounts of [(batho)3:Zn2+] and PEG-6000. Efficient (95-97%) chelator recycling was achieved by recrystallization. Chelator leaching into purified AchE-Fc was estimated to be ~0.3% relative to the total amount used. Taken together, this novel procedure has the potential to provide an economical and practical avenue for the industrial purification of Fc-fusion proteins.
| S-EPMC11843901 | biostudies-literature