Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.
Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico).
Recombinant antibody fragments, for example, the classic monovalent single-chain antibody (scFv), are emerging as credible alternatives to monoclonal antibody (mAb) products. scFv fragments maintain a diverse range of potential applications in biotechnology and can be implemented as powerful therapeutic and diagnostic agents. As such, a variety of hosts have been used to produce antibody fragments resulting in varying degrees of success. Yeast, Saccharomyces cerevisiae, is an attractive host due to quality control mechanisms of the secretory pathway that ensure secreted proteins are properly folded. However, the expression of a recombinant protein in yeast is not trivial; neither are the quality control mechanisms the cell initiates to respond to overwhelming stress, such as an increased protein load, simplistic. The endoplasmic reticulum (ER) is a dynamic organelle, capable of sensing and adjusting its folding capacity in response to increased demand. When protein abundance or terminally misfolded proteins overwhelm the ER’s capacity, the unfolded protein response (UPR) is activated. In the guidelines presented here, we discuss varying aspects of quality control, its modulation, and ways to design appropriate constructs for yeast recombinant protein expression. Furthermore, we have provided protocols and methods to monitor intracellular protein expression and trafficking as well as evaluation of the UPR, with essential controls. The latter part of this chapter will review considerations for the experimental design of microarray and quantitative polymerase chain reaction (q-PCR) techniques while suggesting appropriate means of data analysis.
The multifactorial nature of disease motivates the use of systems-level analyses to understand their pathology. We used a systems biology approach to study tau aggregation, one of the hallmark features of Alzheimer's disease. A mathematical model was constructed to capture the current state of knowledge concerning tau's behavior and interactions in cells. The model was implemented in silico in the form of ordinary differential equations. The identifiability of the model was assessed and parameters were estimated to generate two cellular states: a population of solutions that corresponds to normal tau homeostasis and a population of solutions that displays aggregation-prone behavior. The model of normal tau homeostasis was robust to perturbations, and disturbances in multiple processes were required to achieve an aggregation-prone state. The aggregation-prone state was ultrasensitive to perturbations in diverse subsets of networks. Tau aggregation requires that multiple cellular parameters are set coordinately to a set of values that drive pathological assembly of tau. This model provides a foundation on which to build and increase our understanding of the series of events that lead to tau aggregation and may ultimately be used to identify critical intervention points that can direct the cell away from tau aggregation to aid in the treatment of tau-mediated (or related) aggregation diseases including Alzheimer's.
Antibody therapeutics continue to represent a significant portion of the biotherapeutic pipeline, with growing promise for bispecific antibodies (BsAbs). BsAbs can target 2 different antigens at the same time, such as simultaneously binding tumor-cell receptors and recruiting cytotoxic immune cells. This simultaneous engagement of 2 targets can be potentially advantageous, as it may overcome disadvantages posed by a monotherapy approach, like the development of resistance to treatment. Combination therapy approaches that modulate 2 targets simultaneously offer similar advantages, but BsAbs are more efficient to develop. Unlike combination approaches, BsAbs can facilitate spatial proximity of targets that may be necessary to induce the desired effect. Successful development of BsAbs requires understanding antibody formatting and optimizing activity for both targets prior to clinical trials. To realize maximal efficacy, special attention is required to fully define pharmacokinetic (PK)/pharmacodynamic (PD) relationships enabling selection of dose and regimen. The application of physiologically based pharmacokinetics (PBPK) has been evolving to inform the development of novel treatment modalities such as bispecifics owing to the increase in our understanding of pharmacology, utility of multiscale models, and emerging clinical data. In this review, we discuss components of PBPK models to describe the PK characteristics of BsAbs and expand the discussion to integration of PBPK and PD models to inform development of BsAbs. A framework that can be adopted to build PBPK-PD models to inform the development of BsAbs is also proposed. We conclude with examples that highlight the application of PBPK-PD and share perspectives on future opportunities for this emerging quantitative tool.
Etanercept has been recently approved in the United States for the treatment of moderate to severe plaque psoriasis in patients aged 4-17 years. The objective of this study was to characterize etanercept pharmacokinetics, immunogenicity, and efficacy in pediatric patients. Data from a phase 3 study and open-label extension study were analyzed. Etanercept serum concentrations in pediatric patients receiving etanercept 0.8 mg/kg (maximum, 50 mg) weekly were compared with adult psoriasis patients and pediatric patients with juvenile idiopathic arthritis (JIA) who received etanercept 0.4 mg/kg twice weekly. The developments of antietanercept antibodies and efficacy based on the Psoriasis Area and Severity Index were evaluated. Steady-state trough etanercept concentrations were similar across visits from weeks 12-48, between patients aged 4-11 and 12-17 years, between pediatric and adult psoriasis patients, and between pediatric patients with psoriasis or JIA. Etanercept serum concentrations and safety profiles were similar in patients with (15.9%) and without antietanercept antibodies. Dosing used in the study provided similar exposures and efficacy across ranges of weight and body mass index. Pharmacokinetic, immunogenicity, and efficacy data support 0.8 mg/kg (maximum, 50 mg) weekly dosing of etanercept in patients aged 4-17 years.
Background: Low-dose interleukin-2 (IL-2) therapy expands regulatory T cells (Tregs) and provides clinical benefit for inflammatory diseases; however, concomitant increases in conventional effector T cells (Tcon) and natural killer (NK) cells may result in toxicity. AMG 592 is an investigational IL-2 mutein designed for greater Treg selectivity and longer half-life compared with recombinant IL-2 (aldesleukin). In preclinical studies and a phase 1, double-blind, placebo (PBO)-controlled first-in-human (FIH) study, we investigated the safety and tolerability of AMG 592 and its effects on expansion of Treg, Tcon, and NK-cells. Methods: AMG 592 activity was assessed as in vitro phosphorylated STAT5 (pSTAT5) in primary human peripheral blood mononuclear cells (PBMC). Treg, Tcon, and NK-cell expansion and cytokine production were assessed after culture of pre-stimulated human PBMC with increasing doses of AMG 592 or aldesleukin. The in vivo effects of AMG 592 on body temperature, C-reactive protein (CRP), and peripheral blood Treg, Tcon, and NK numbers were evaluated in cynomolgus monkeys after escalating single SC doses of AMG 592 or 5 consecutive daily SC doses of aldesleukin. In the FIH study, healthy volunteers in 8 dose cohorts received a single SC ascending dose of AMG 592 (n=6 per dose) or placebo (n=2 per dose) and were evaluated for safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and cytokine production for 28 days. Results: In human PBMC cultures, AMG 592 caused more selective Treg response (pSTAT5 and proliferation) and lower production of pro-inflammatory cytokines than aldesleukin. Dose-dependent expansion of FoxP3+ Tregs in aldesleukin-treated cynomolgus monkeys was accompanied by increased body temperature and CRP; however, AMG 592 caused Treg expansion without significant effects on body temperature or CRP. In the ongoing FIH study, AMG 592 was well tolerated, with no serious adverse events (AEs). The most common AE across treatment arms was grade 1 painless erythema at or near the injection site that resolved without treatment. Preliminary PK results indicate dose-related increases in AMG 592 serum exposure. AMG 592 caused a robust, dose-dependent expansion of Tregs relative to Tcon in all treated individuals. Expanded Tregs had increased levels of CD25 and Foxp3, and were enriched for recent thymic emigrants. At the highest dose, the increase in the Treg:Tcon ratio peaked at day 8 (~4-fold vs baseline) and remained elevated up to day 29. Treg expansion by AMG 592 was highly selective, with no directional change in NK-cell numbers and minimal increase in Tcon. Moreover, there were no increases in the serum pro-inflammatory cytokines IL-6, TNFα, or IFN-γ above the limits of detection. Conclusion: AMG 592 caused a dose-dependent, selective expansion of Tregs in healthy volunteers. The lack of pro-inflammatory cytokines and reduced markers of inflammation by AMG 592 compared with aldesleukin suggests a wider therapeutic margin. The sustained Treg elevation compared with aldesleukin suggests less frequent dosing may be feasible. Further investigation of the ability of AMG 592 to restore immune homeostasis by Tregs in inflammatory and autoimmune diseases is warranted. Disclosures Tchao: Amgen Inc.: Employment, Equity Ownership. Gorski: Amgen Inc.: Employment, Equity Ownership. Yuraszeck: Amgen Inc.: Employment, Equity Ownership. Sohn: Amgen Inc.: Employment, Equity Ownership. Ishida: Amgen Inc.: Employment, Equity Ownership. Wong: Amgen Inc.: Employment, Equity Ownership. Park: Amgen Inc.: Employment, Equity Ownership.
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