Anti-CD45RB Monoclonal Antibody Prolongs Renal Allograft Survival in Cynomolgus Monkeys

Chen, G.; Luke, Patrick; Yang, Hongji; Visser, Lydia; Sun, Hongtao; García, Bertha; Qian, Heying; Xiang, Ying; Huang, Xiaohang; Liu, W.; Senaldi, Giorgio; Schneider, Anneliese; Poppema, Sibrand; Wang, H.; Jevnikar, Anthony M.; Zhong, Robert

doi:10.1111/j.1600-6143.2006.01598.x

Cited by 25 publications

(19 citation statements)

References 42 publications

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“…These observations led to the hypothesis that transient anti-CD45RC mAb, which depletes CD45RC + cells, could induce not only transplant tolerance, but also favor CD45RC low/-Treg generation. Tolerance induction in two different alloincompatible rat strain combinations suggests that targeting the CD45RC molecule could be superior to anti-CD45RB mAb therapy, which resulted in a significant but only moderate increase of allograft survival in animal models, along with chronic rejection (40)(41)(42)(43)(44)(45)(46). Indeed, our results suggest that anti-CD45RB mAb could target all Foxp3 + and CD8 + Tregs that express this marker (47,48).…”

Section: Discussionmentioning

confidence: 88%

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

Picarda¹,

Bézie²,

Boucault³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 88%

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

Picarda¹,

Bézie²,

Boucault³

et al. 2017

JCI Insight

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“…ATG has been shown to prolong primate graft survival (Thomas et al 1978); however, its dosing requirements, halflife, and specificity differ so significantly from that seen in humans (the species to which ATG is raised) that it is unlikely that ATG's behavior in NHPs is a satisfactory surrogate for its use in the clinic. ATG fails to induce tolerance in most models, and is thus used primarily as induction therapy followed by some form of maintenance therapy, a variety of which have been successful (Hirshberg et al 2003;Liu et al 2007). However, a study by Haanstra et al (2006) found that ATG combined with costimulation blockade shortened the time to rejection, possibly owing to decreased intragraft inhibitory molecules.…”

Section: Depletionmentioning

confidence: 99%

“…However, use of a nondepleting antibody, OKT4A, only modestly prolonged graft survival (Cosimi et al 1990;Wee et al 1992;Mourad et al 1998). Depletion based on another potential target, CD45RB, has been shown to prolong graft survival in cynomolgus macaques (Chen et al 2007). B cells have also been targeted in depletional studies, with the agent rituximab showing prolongation of graft survival in primate islet (Liu et al 2007) and cardiac models (Kelishadi et al 2010).…”

Section: Depletionmentioning

confidence: 99%

Primate Models in Organ Transplantation

Anderson

Kirk

2013

Cold Spring Harbor Perspectives in Medicine

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Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic-and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.A nimal experimentation has long provided a rational basis for the translation of treatments and techniques from the bench to the bedside. In general, all first-in-human trials require preparative animal experimentation to allow patients to make truly informed decisions about their participation. Properly designed animal studies in relevant species provide the necessary background experience with a novel approach to reasonably anticipate the efficacy or, at the very least, safety of a planned intervention. As such, they serve as a foundation on which human trials can be ethically designed, particularly in fields such as immunology, in which the complexity of the interactions involved has prevented the development of any sufficiently predictive in vitro model. Although animal models are far superior to in vitro models in projecting the potential of an approach, it must be recognized that they do not mimic clinical transplantation precisely, and thus cannot be expected to forecast the ultimate experience in humans.The mouse model has formed the backbone of medical research and development for many years owing to the relative ease of breeding and genetic manipulation of the animals at a comparatively low cost. For immunology research, the mouse immune system offers sufficient homology for pathway determination and mechanistic studies, and indeed represents the ideal platform for this type of endeavor. In contrast, the large animal models (dog, pig, and primate) are significantly more expensive and, with the exception of inbred miniature swine (Sachs 1992;Mezrich et al. 2003), exhibit increased genetic diversity, making definitive mechanistic studies much more difficult, if not impossible. However, this complexity makes large animals suited to preclinical studies, in which the addition of often-unanticipated variables allows for the examination of practicality, safety, and generalized efficacy. In general, mice define pathways, and large animal models help establish whether a particular pathway's effect is suffi-

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“…24 The underlying mechanism remains largely unclear. Based on the hypothesis that the Ab might influence the activity of the enzyme, we performed an in vitro phosphatase assay to investigate the action of anti-CD45RB mAb (6G3) on the enzymatic activity of CD45.…”

Section: Anti-cd45rb Ab Increases Cd45 Phosphatase Activity In Restinmentioning

confidence: 99%

“…Indeed, antibodies (Abs) to CD45 have been effective in preventing rejection of transplants in several different animal models. [20][21][22][23] We have reported earlier that a mouse anti-human CD45RB Ab (6G3) that also recognizes monkey CD45RB has similar effects on monkey and human cells in vitro and also prevents rejection in an allogeneic nonhuman primate renal transplantation model, 24 although the molecular mechanism behind this action is unclear. This consideration prompted us to directly assess the effects of antihuman CD45RB Ab (6G3) treatment on CD45 enzymatic activity, and we observed direct stimulation of CD45 tyrosine phosphatase activity.…”

Section: Introductionmentioning

confidence: 99%

Extracellular ligation-dependent CD45RB enzymatic activity negatively regulates lipid raft signal transduction

Parikh¹,

Poppema

Peppelenbosch³

et al. 2009

Blood

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CD45 is the most prominent membrane protein on lymphocytes. The function and regulation of this protein tyrosine phosphatase remain largely obscure, mainly because of the lack of a known ligand, and it still remains unknown whether such tyrosine phosphatases are subject to extracellular control at all. We report that an anti-CD45RB antibody (Ab) that prevents rejection and induces tolerance activates CD45RB tyrosine phosphatase enzymatic activity in T lymphocytes, allowing us to directly monitor the effects of increased CD45RB activity on signal transduction. Using both kinase substrate peptide arrays as well as conventional biochemistry, we also provide evidence of the various kinases involved in bringing about the inhibitory effect of this Ab on CD3-induced T-cell receptor signaling. Furthermore, we report that activated CD45RB translocates to lipid rafts and interferes with lipid raft localization and activation state of CD45 substrate Lck. Thus, these findings indeed prove that CD45 is subject to extracellular control and also define a novel mechanism by which receptor tyrosine phosphatases control lymphocyte biology and provide further insight into the intracellular signaling pathways effected by anti-CD45RB mono- IntroductionProtein phosphorylation plays a crucial role in regulating almost every aspect of cellular physiology, tyrosine phosphorylation even more so, as it is extensively used only in eukaryotes acting as a critical control point for important cellular processes, such as communication between and within cells, proliferation or differentiation, cell death, motility, and transportation of molecules into or out of cells. [1][2][3] The phosphorylation status of these control points is tightly regulated by the antagonistic activities of protein kinases and protein phosphatases. Abnormal functioning of protein kinases and phosphatases is implicated in various human diseases, ranging from cancer to immune deficiencies. 4 Strikingly, whereas the action of many different protein kinases is now fairly well understood for a large variety of biologic events, the role of most protein phosphatases remains unclear.CD45 was one of the first protein tyrosine phosphatases found to be expressed on all nucleated hematopoietic cells as a major high molecular weight leukocyte cell surface antigen. [5][6][7][8] Structural analysis of the CD45 cytoplasmic region has shown that the intracellular tail of CD45 contains 2 homologous domains. 7 The first membrane, proximal phosphatase domain, has phosphatase activity, whereas the second domain is thought to be required for proper folding and substrate recruitment. 9 Six different isoforms, varying in molecular weight (180-220 kDa), antigenicity, and glycosylation have been identified and characterized. 10 Different isoforms may exert different functions in cellular physiology; however, this issue is still under debate. Little evidence for clear functional differences between isoforms has emerged from experiments using transgenic mice expressing single isoforms of CD45 on...

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Anti-CD45RB Monoclonal Antibody Prolongs Renal Allograft Survival in Cynomolgus Monkeys

Cited by 25 publications

References 42 publications

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

Primate Models in Organ Transplantation

Extracellular ligation-dependent CD45RB enzymatic activity negatively regulates lipid raft signal transduction

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