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Targeting Anti-TGF-? Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

ABSTRACT: Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-? After systemic injection of the bispecific TGF-? + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-? mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-? mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-? mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.

SUBMITTER: McGaraughty S

PROVIDER: S-EPMC5698069 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Targeting Anti-TGF-<i>β</i> Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

McGaraughty Steve S Davis-Taber Rachel A RA Zhu Chang Z CZ Cole Todd B TB Nikkel Arthur L AL Chhaya Meha M Doyle Kelly J KJ Olson Lauren M LM Preston Gregory M GM Grinnell Christine M CM Salte Katherine M KM Giamis Anthony M AM Luo Yanping Y Sun Victor V Goodearl Andrew D AD Gopalakrishnan Murali M Lacy Susan E SE

Journal of the American Society of Nephrology : JASN 20170821 12

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of ren ...[more]

PMID: 28827403

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Project description:Purpose: To find out the patients who are most sensitive and effective to the anti-PD-L1 and TGF-β bifunctional fusion protein in the treatment of recurrent cervical cancer. Patients and methods: We report two cases of recurrent cervical cancer treated with the anti-PD-L1 and TGF-β bifunctional fusion protein. We described the clinical course, clinical characteristics, and genetic characteristics of the two patients, and analyzed the changes of gene expression in the two patients after treatment. Results: Although PD-L1 expression and HPV status were same in the two patients, the treatment effect of two patients with recurrent cervical cancer was different, according to the evaluation of enhanced computed tomography (CT), one was partial response (PR) and the other was progressive disease (PD), which may indicate that PD-L1 expression and HPV status of patients is not enough to predict the effectiveness of the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Then, we demonstrated that the changes of peripheral blood lymphocytes of two patients during the treatment had different trends. Moreover, number of alterable genes in PR patient is much greater than that in PD patient, indicating PR patient may be more sensible to the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Total 4844 genes changing-fate gene set selected which is believed conducting anti-cancer function during the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Furthermore, we identified that changing-fate genes were correlated with female reproductive organ cancer, infectious disease, inflammatory disease, immune system, indicating these genes may conducting anti-cancer, anti-inflammation and immune function. Conclusion: Anti-PD-L1 and TGF-β bifunctional fusion protein is feasible for the treatment of recurrent cervical cancer. Multi-center, large-sample prospective clinical studies are still needed to further explore the efficacy of anti-PD-L1 and TGF-β bifunctional fusion protein in recurrent cervical cancer and screen appropriate patients, so as to achieve the maximum survival benefit of patients.

Project description:BackgroundTherapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance.MethodsBased on the Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment.ResultsYM101 could bind to TGF-β and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-β and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-β and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of 'hot tumor': increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101.ConclusionOur results demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.

Dataset Information

Targeting Anti-TGF-? Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

Publications

Targeting Anti-TGF-<i>β</i> Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

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