TNF-  neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome

CD97 is a member of the EGF-TM7 family of adhesion class receptors, with a proposed role in inflammatory cell recruitment. Neutralization of murine CD97 with the anti-mCD97 mAb 1B2 was efficacious in prevention of murine collagen-induced arthritis, a model with features resembling rheumatoid arthritis. Here, the therapeutic potential of neutralizing CD97 in arthritis was studied with emphasis on the 1B2 pharmacokinetics. Mice with established arthritis were treated with anti-mCD97 or anti-TNF-α serum. Ab pharmacokinetics and biodistribution were studied in diseased and nondiseased mice using labeled 1B2. The impact of CD97 expression on Ab pharmacokinetics was studied using CD97 knockout mice. Treatment with 1B2 showed an efficacy comparable to anti-TNF-α treatment. Pharmacokinetic analysis of 1B2 in wild-type and CD97 knockout mice indicated a dose-dependent Ab clearance, due to specific interaction with CD97. Biodistribution studies showed accumulation of 1B2 in spleen and lung. In vitro studies using murine splenocytes revealed that CD97 when bound to Ab was internalized. Moreover, soluble CD97 was detected in the supernatant, suggesting Ag shedding. Finally, in arthritic mice, higher levels of soluble CD97 were found and 1B2 treatment led to specific targeting of inflamed paws, resulting in a higher clearance rate of 1B2 in arthritic mice than in wild-type mice. In conclusion, our data support a therapeutic value of CD97 neutralization in experimental arthritis. The pharmacokinetic profile of the 1B2 Ab illustrates the complexity of Ab elimination from an organism and stresses the importance of understanding Ag-Ab interactions when developing therapeutic mAbs.

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“…This difference in efficacy may be explained by differences in free levels of TNF-␣ between RA and systemic inflammatory response syndrome (30).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2

Groot¹,

Vogel²,

Dulos³

et al. 2009

The Journal of Immunology

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“…Due to the rapid half-life of the molecule, it is feasible that TNF-α bound to dTNFR will be rapidly eliminated by this route. By contrast, etanercept-like molecules incorporating the immunoglobulin Fc portion have a long half-life in the blood and bound TNF-α is retained in the system and not rapidly cleared [49]. When delivered as protein, a molecule that has a long half-life and therefore reduces the frequency of re-administration is preferred; but for gene therapy, in which a molecule is continuously produced, it may be preferable for the molecule to be rapidly excreted [50].…”

Section: Discussionmentioning

confidence: 99%

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et al. 2007

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Inhibition of tumour necrosis factor (TNF)-alpha with biological molecules has proven an effective treatment for rheumatoid arthritis, achieving a 20% improvement in American College of Rheumatology score in up to 65% of patients. The main drawback to these and many other biological treatments has been their expense, which has precluded their widespread application. Biological molecules could alternatively be delivered by gene therapy as the encoding DNA. We have developed novel plasmid vectors termed pGTLMIK and pGTTMIK, from which luciferase and a dimeric TNF receptor II (dTNFR) are respectively expressed in a doxycycline (Dox)-regulated manner. Regulated expression of luciferase from the self-contained plasmid pGTLMIK was examined in vitro in a variety of cell lines and in vivo following intramuscular delivery with electroporation in DBA/1 mice. Dox-regulated expression of luciferase from pGTLMIK of approximately 1,000-fold was demonstrated in vitro, and efficient regulation was observed in vivo. The vector pGTTMIK encoding dTNFR was delivered by the same route with and without administration of Dox to mice with collagen-induced arthritis. When pGTTMIK was delivered after the onset of arthritis, progression of the disease in terms of both paw thickness and clinical score was inhibited when Dox was also administered. Vectors with similar regulation characteristics may be suitable for clinical application.

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“…We captured TNF neutralization-associated reactions (schematically shown in Figure 2B) in our model, including reversible binding of drug to mTNF and sTNF [47], [48], release of drug-bound mTNF into extracellular spaces due to TACE activity, and drug or TNF/drug complex degradation [49] based on mass action kinetics as shown in Table 2. Definitions and values of drug-specific parameters are given in Table 4.…”

Section: Methodsmentioning

confidence: 99%

Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma

et al. 2010

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Tuberculosis (TB) granulomas are organized collections of immune cells comprised of macrophages, lymphocytes and other cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro-inflammatory cytokine, tumor necrosis factor-α (TNF). To characterize mechanisms that control TNF availability within a TB granuloma, we developed a multi-scale two compartment partial differential equation model that describes a granuloma as a collection of immune cells forming concentric layers and includes TNF/TNF receptor binding and trafficking processes. We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads. Using our model, we then demonstrated that the organization of immune cells within a TB granuloma as well as TNF/TNF receptor binding and intracellular trafficking are two important factors that control TNF availability and may spatially coordinate TNF-induced immunological functions within a granuloma. Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry. To further elucidate the role of TNF in the process of granuloma development, our modeling and experimental findings on TNF-associated molecular scale aspects of the granuloma can be incorporated into larger scale models describing the immune response to TB infection. Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.

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TNF- neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome

Abstract: These results may explain the effectiveness of TNF-alpha blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.

Cited by 32 publications

References 52 publications

Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2

Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2

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Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma

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