First-in-Human Study of the Safety and Efficacy of TOL101 Induction to Prevent Kidney Transplant Rejection

Flechner, Stuart M.; Mulgoankar, S.; Melton, L. A.; Waid, Thomas; Ágarwal, Avinash Kumar; Miller, Stephen D.; Fokta, F.; Getts, Meghann Teague; Frederick, Todd; Herrman, Jan; Puisis, J. P.; O’Toole, L.; Sung, Randall S.; Shihab, Fuad S.; Wiseman, Alexander C.; Getts, Daniel R.

doi:10.1111/ajt.12698

Cited by 13 publications

(5 citation statements)

References 29 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, in an effort to minimize T cell activation and its consequences that were observed with higher affinity IgG antibodies, this IgM was explored as a lower affinity/lower avidity therapeutic targeting this antigen. In a Phase 2 study [ 178 ], patients received five daily doses, up to 42 mg/day, and prolonged CD3 modulation occurred at doses above 28 mg. There were no cases of patient or graft loss, the treatments were well tolerated, and CD3 levels recovered within seven days after the cessation of therapy.…”

Section: Therapeutic Uses Of Igm Antibodiesmentioning

confidence: 99%

Structure, Function, and Therapeutic Use of IgM Antibodies

et al. 2020

View full text Add to dashboard Cite

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

show abstract

Section: Therapeutic Uses Of Igm Antibodiesmentioning

confidence: 99%

Structure, Function, and Therapeutic Use of IgM Antibodies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It is now no longer in production because of waning utilization, primarily because of significant side effects related to the mitogenicity associated with its murine source. This early experience led to the development of humanized forms of anti-TCR-based agents in an effort to reduce this mitogenicity as well as other anti-TCR mAbs that targeted other receptor subunits (10)(11)(12). These next generation therapeutics were subsequently forwarded for the treatment of newonset diabetes and as induction agents in kidney transplantation but have been hindered by ongoing safety and efficacy issues.…”

Section: Agents Targeting Signalmentioning

confidence: 99%

Immunosuppressive Medications

Wiseman¹

2016

Clinical Journal of the American Society of Nephrology

202

165

View full text Add to dashboard Cite

Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.

show abstract

“…(108, 111, 170, 171) Future work that may translate into targeted therapy is focused on developing and testing novel inhibitors to pathogenic mediators in SJS/TEN including a monoclonal antibody targeting granulysin and a monoclonal antibody targeting the TCRαβ subunits to disrupt TCR signaling. (172, 173) Another insight into the immunopathogenesis of SJS/TEN has come from studies demonstrating that interaction of annexin A1 with the formyl peptide receptor 1, expressed on the surface of keratinocytes obtained from patients with SJS/TEN but not present on control keratinocytes, is a key mediator of keratinocyte necroptosis in SJS/TEN. (174)…”

Section: Introductionmentioning

confidence: 99%

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

White

Abe

Ardern‐Jones

et al. 2018

The Journal of Allergy and Clinical Immunology: In Practice

149

132

View full text Add to dashboard Cite

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

show abstract

First-in-Human Study of the Safety and Efficacy of TOL101 Induction to Prevent Kidney Transplant Rejection

Cited by 13 publications

References 29 publications

Structure, Function, and Therapeutic Use of IgM Antibodies

Structure, Function, and Therapeutic Use of IgM Antibodies

Immunosuppressive Medications

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Contact Info

Product

Resources

About