Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease

Sun, Baodong; Banugaria, Suhrad G.; Prater, Sean N.; Patel, Tulsi; Fredrickson, Keri; Ringler, Douglas J.; Fougerolles, Antonin de; Rosenberg, Amy S.; Waldmann, Herman; Kishnani, Priya S.

doi:10.1016/j.ymgmr.2014.08.005

Cited by 14 publications

(12 citation statements)

References 26 publications

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“…This is most likely the result of injecting mice with an ENPP1 protein that is recombinant and from a different species. Numerous rodent studies have shown that co-administration of anti-CD4 monoclonal antibody (mAb) can prevent ADA development in response to a protein replacement therapy and therefore this strategy was utilized here ( Rice and Bucy, 1995 ; Sun et al, 2014 ). Flow cytometry analysis confirmed >90% depletion of CD4 + T cells in peripheral blood from Asj-2J mice 7 days after a single 300 µg injection with an anti-CD4 mAb ( …”

Section: Resultsmentioning

confidence: 99%

ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy

Khan

Sinkevicius

Vong

et al. 2018

Disease Models &Amp; Mechanisms

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Generalized arterial calcification of infancy (GACI) is a rare, life-threatening disorder caused by loss-of-function mutations in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), which normally hydrolyzes extracellular ATP into AMP and pyrophosphate (PPi). The disease is characterized by extensive arterial calcification and stenosis of large- and medium-sized vessels, leading to vascular-related complications of hypertension and heart failure. There is currently no effective treatment available, but bisphosphonates – nonhydrolyzable PPi analogs – are being used off-label to reduce arterial calcification, although this has no reported impact on the hypertension and cardiac dysfunction features of GACI. In this study, the efficacy of a recombinant human ENPP1 protein therapeutic (rhENPP1) was tested in Enpp1asj-2J homozygous mice (Asj-2J or Asj-2J hom), a model previously described to show extensive mineralization in the arterial vasculature, similar to GACI patients. In a disease prevention study, Asj-2J mice treated with rhENPP1 for 3 weeks showed >95% reduction in aorta calcification. Terminal hemodynamics and echocardiography imaging of Asj-2J mice also revealed that a 6-week rhENPP1 treatment normalized elevated arterial and left ventricular pressure, which translated into significant improvements in myocardial compliance, contractility, heart workload and global cardiovascular efficiency. This study suggests that ENPP1 enzyme replacement therapy could be a more effective GACI therapeutic than bisphosphonates, treating not just the vascular calcification, but also the hypertension that eventually leads to cardiac failure in GACI patients.

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Section: Resultsmentioning

confidence: 99%

ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy

Khan

Sinkevicius

Vong

et al. 2018

Disease Models &Amp; Mechanisms

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“…We also found that the induction of anti-GAA IgG1 responses assessed at 4 weeks after injection of rhGAA in Pompe animals was prevented by administration of a nonlytic anti-CD4 antibody given prior to ERT. 24 Given this effect of anti-CD4 to prevent immune responses, we elected The comparison was performed between the vector alone (G2) and vector plus three doses of anti-CD4 mAb (G4) groups. Group size as follows: G1 (n = 7), G2 (n = 11), G3 (n = 9), and G4 (n = 14).…”

Section: Resultsmentioning

confidence: 99%

“…[19][20][21][22][23] The use of nondepleting anti-CD4 mAb has also shown to decrease the immune response to introduced rhGAA in Pompe disease mice. 24 Anti-CD4 mAb in combination with cyclosporine was effective at suppressing anticapsid antibodies in response to administration of an AAV vector, although the effect was transient. 25 In the present study, we describe the inhibition of T helper cells by anti-CD4 mAb to achieve the control of immune responses to an AAV vector in GAA-KO mice.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Efficacy from Gene Therapy in Pompe Disease Using Coreceptor Blockade

Han

Brooks

et al. 2015

Human Gene Therapy

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Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid a-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease.

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“…Central tolerance has been induced in the C57Bl/6 N mouse by using an adenovirusassociated vector-expressing GAA (Chu et al 2010) to alter thymic GAA expression. Peripheral tolerance secondary to antigen specific Treg generation has been achieved with transplacental transfer of Fc-fused antigens (Gupta et al 2015), the useofIVIg(Loubakietal2015; Cousens et al 2014) and nondepleting anti-CD4 monoclonal antibodies (Sun et al 2014). More broad based therapies including the use of anti-CD3 antibodies (Ohashi et al 2012) and the SLE licensed, anti B cell activating factor (BAFF) ha veal so been studied with both ameliorating IRRS and ADA.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders

Broomfield

Jones

Hughes

et al. 2016

J of Inher Metab Disea

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In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.

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Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease

Cited by 14 publications

References 26 publications

ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy

ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy

Enhanced Efficacy from Gene Therapy in Pompe Disease Using Coreceptor Blockade

The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders

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