A predictive biomimetic model of cytokine release induced by TGN1412 and other therapeutic monoclonal antibodies

Dhir, Vipra; Fort, Madeline M.; Mahmood, Ayesha; Higbee, Russell G.; Warren, W. L.; Narayanan, Padma K.; Wittman, Vaughan

doi:10.3109/1547691x.2011.613419

Cited by 36 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro modelling of antigenicity utilizes T cell assays, B cell assays, and mimotopes to identify potentially immunogenic epitopes [33, 34], whereas in vitro characterization of immunogenic response from serum samples includes qualitative and quasiquantitative immunoassays such as enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and immunoradiometric assays (IRMAs) [35]. Cell-based assays remain a popular choice for modeling antigenicity via the immunophenotyping, proliferation tracking, and cytokine secretion profiling of immune cells [36, 37].…”

Section: Immunogenic Risk Factors and The Need For Predictive Toolsmentioning

confidence: 99%

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Smith

Manoli

Jaw

et al. 2016

Journal of Immunology Research

View full text Add to dashboard Cite

Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.

show abstract

Section: Immunogenic Risk Factors and The Need For Predictive Toolsmentioning

confidence: 99%

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Smith

Manoli

Jaw

et al. 2016

Journal of Immunology Research

View full text Add to dashboard Cite

show abstract

“…Attempts to model in vivo presentation of TGN1412 employed a co-culture of human endothelial cell monolayers with donor lymphocytes have been shown to result in pro-inflammatory cytokine release, particularly IL-6, IL-8, and TNF α (Stebbings et al, 2007; Findlay et al, 2011b; Dhir et al, 2012). It has subsequently been reported that the cytokine profile of this model does not fully match that of the trial volunteers or assays with immobilized TGN1412, as only low levels of the cytokines IL-2 and IFN γ are produced (Findlay et al, 2011b).…”

Section: Assay Refinements and Co-culture Alternativesmentioning

confidence: 99%

After TGN1412: Recent developments in cytokine release assays

Stebbings

Eastwood

Poole

et al. 2012

Journal of Immunotoxicology

View full text Add to dashboard Cite

The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a ‘Cytokine Storm’. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.

show abstract

“…Recently, several groups have published on in vitro assays that may offer predictivity for in vivo cytokine release (Dhir et al 2012;Findlay et al 2011).…”

Section: Cytokine Releasementioning

confidence: 99%

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Everds

Tarrant²

2013

Toxicol Pathol

View full text Add to dashboard Cite

Biotherapeutics are expanding the arsenal of therapeutics available for treating and preventing disease. Although initially thought to have limited side effects due to the specificity of their binding, these drugs have now been shown to have potential for adverse drug reactions including effects on peripheral blood cell counts or function. Hematotoxicity caused by a biotherapeutic can be directly related to the activity of the biotherapeutic or can be indirect and due to autoimmunity, biological cascades, antidrug antibodies, or other immune system responses. Biotherapeutics can cause hematotoxicity primarily as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses, and sequelae from initiating cytokine and complement cascades. The underlying pathogenesis of biotherapeutic-induced hematotoxicity often is poorly understood. Nonclinical studies have generally predicted clinical hematotoxicity for recombinant cytokines and growth factors. However, most hematologic liabilities of biotherapeutics are not based on drug class but are species specific, immune-mediated, and of low incidence. Despite the potential for unexpected hematologic toxicity, the risk-benefit profile of most biotherapeutics is favorable; hematologic effects are readily monitorable and managed by dose modification, drug withdrawal, and/or therapeutic intervention. This article reviews examples of biotherapeutics that have unexpected hematotoxicity in nonclinical or clinical studies.

show abstract

A predictive biomimetic model of cytokine release induced by TGN1412 and other therapeutic monoclonal antibodies

Cited by 36 publications

References 25 publications

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

After TGN1412: Recent developments in cytokine release assays

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Contact Info

Product

Resources

About