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Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

ABSTRACT: Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-? (?-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-?-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-?-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-? (?-TGF-?) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.

SUBMITTER: Katsumata K

PROVIDER: S-EPMC6834392 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

Katsumata Kiyomitsu K Ishihara Jun J Mansurov Aslan A Ishihara Ako A Raczy Michal M MM Yuba Eiji E Hubbell Jeffrey A JA

Science advances 20191106 11

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the ...[more]

PMID: 31723606

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Project description:BackgroundAlthough disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-? antibody (?-TNF) are injected systemically. Given that ?-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce ?-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to ?-TNF antibodies in a RA model.Methods?-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated ?-TNF (PlGF-2123-144-?-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-?-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse.ResultsPlGF-2123-144 peptide conjugation conferred ?-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-?-TNF locally injected at a paw in the CAIA model was retained for at least 96?h at the injection site, whereas unmodified ?-TNF was dispersed rapidly after injection. Local treatment with unmodified ?-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-?-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose.ConclusionThese data demonstrate that retention of ?-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

Project description:BackgroundUncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined.ResultsIn this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not.ConclusionThe i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.

Project description:We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment.Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations.We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells.To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.

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Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

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Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

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