Identification and validation of an immune-derived multiple programmed cell death index for predicting clinical outcomes, molecular subtyping, and drug sensitivity in lung adenocarcinoma.

OBJECTIVES: Comprehensive cross-interaction of multiple programmed cell death (PCD) patterns in the patients with lung adenocarcinoma (LUAD) have not yet been thoroughly investigated. METHODS: Here, we collected 19 different PCD patterns, including 1911 PCD-related genes, and developed an immune-derived multiple programmed cell death index (MPCDI) based on machine learning methods. RESULTS: Using the median MPCDI scores, we categorized the LUAD patients into two groups: low-MPCDI and high-MPCDI. Our analysis of the TCGA-LUAD training cohort and three external GEO cohorts (GSE37745, GSE30219, and GSE68465) revealed that patients with high-MPCDI experienced a more unfavorable prognosis, whereas those with low-MPCDI had a better prognosis. Furthermore, the results of both univariate and multivariate Cox regression analyses further confirmed that MPCDI serves as a novel independent risk factor. By combining clinical characteristics with the MPCDI, we constructed a nomogram that provides an accurate and reliable quantitative tool for personalized clinical management of LUAD patients. The findings obtained from the analysis of C-index and the decision curve revealed that the nomogram outperformed various clinical variables in terms of net clinical benefit. Encouragingly, the low-MPCDI patients are more sensitive to commonly used chemotherapy drugs, which suggests that MPCDI scores have a guiding role in chemotherapy for LUAD patients. CONCLUSION: Therefore, MPCDI can be used as a novel clinical diagnostic classifier, providing valuable insights into the clinical management and clinical decision-making for LUAD patients.

FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation.

On May 25th, 2022, FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) extending the indication in patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) in older adults or those with comorbidities to include the combination with azacitidine. The efficacy of ivosidenib in combination with azacitidine was evaluated in Study AG120-C-009, a phase 3, multicenter, double-blind, randomized (1:1), controlled study of ivosidenib or matched placebo in combination with azacitidine in adults with previously untreated AML with an IDH1 mutation who were 75 years or older or had comorbidities that precluded use of intensive induction chemotherapy. Efficacy was established based on improved event-free survival (EFS) and overall survival (OS) on the ivosidenib + azacitidine arm (HR 0.35, 95% CI 0.17, 0.72, p= 0.0038 and HR 0.44, 95% CI 0.27, 0.73, p=0.0010), respectively. Furthermore, the rate and duration of complete remission (CR) were improved with ivosidenib versus placebo (CR 47% versus 15%, 2-sided p<0.0001; median duration of CR not estimable [NE] [95% CI 13.0, NE] months versus 11.2 [95% CI 3.2, NE] months). The safety profile of ivosidenib in combination with azacitidine was consistent with that of ivosidenib monotherapy, with important adverse reactions including differentiation syndrome (15%) and QT interval prolongation (20%).

An MRI-only Three-dimensional Cephalometry Protocol based on the Integrated and Modular Architecture of the Human Head.

BACKGROUND: Currently, three-dimensional cephalometry measurements are mainly based on cone beam computed tomography (CBCT), which has limitations of ionizing radiation, lack of soft tissue information, and lack of standardization of median sagittal plane establishment. OBJECTIVES: This study investigated magnetic resonance imaging (MRI)-only based 3D cephalometry measurement based on the integrated and modular characteristics of the human head. METHODS: Double U-Net CycleGAN was used for CT image synthesis from MRI. This method enabled the synthesis of a CT-like image from MRI and measurements were made using 3D slicer registration and fusion. RESULTS: A protocol for generating and optimizing MRI-based synthetic CT was described and found to meet the precision requirements of 3D head measurement using MRI midline positioning methods reported in neuroscience to establish the median sagittal plane. An MRI-only reference frame and coordinate system were established enabling an MRI-only cephalometric analysis protocol that combined the dual advantages of soft and hard tissue display. The protocol was devised using data from a single volunteer and validation data from a larger sample remains to be collected. CONCLUSION: The reported method provided a new protocol for MRI-only cephalometric analysis of craniofacial growth and development, malformation occurrence, treatment planning, and outcomes.

Anterior cerebral falx plane in MR images to estimate the craniofacial midline.

Multiple methods have been proposed for evaluating the symmetry of facial contour by utilizing the median sagittal plane of the skull as a reference and measuring the maxillofacial region. To replace the manual mark point analysis method, we used the anterior cerebral falx plane in MRI images as an indicator of the craniofacial midline. The MRI examination data of 30 individuals were analyzed with a MeVisLab workstation. Two independent examiners performed 15 anthropometric measurements (4 angular, 11 linear) and compared the MRI-based anterior cerebral falx plane with the manual mark point analysis of the craniofacial midline estimation. All measurements were repeated after 3 weeks. Statistical analyses included the repeatability and reproducibility of the 2 methods based on intra-observer and inter-observer correlation coefficients (ICCs), respectively. Precision was estimated by intergroup comparison of the coefficient of variation. The anterior falx plane derived from the MRI data resulted in an intra-observer ICC of 0.869 ± 0.065 (range 0.733-0.936) and inter-observer ICC of 0.876 ± 0.0417 (0.798-0.932) for all measurements, showing significant correlations with the ICC values obtained by the mark point method (p < 0.05). The coefficient of variation showed that the precisions of the 2 methods were statistically comparable. We conclude that, for MRI-based craniofacial midline estimation, measurements made using the anterior cerebral falx plane are as precise, repeatable, and reproducible as those using the manual mark point analysis method. It has a high potential for application in radiation-free 3-dimensional craniofacial analysis.

Anatomical network modules of the human central nervous-craniofacial skeleton system.

Anatomical network analysis (AnNA) is a systems biological framework based on network theory that enables anatomical structural analysis by incorporating modularity to model structural complexity. The human brain and facial structures exhibit close structural and functional relationships, suggestive of a co-evolved anatomical network. The present study aimed to analyze the human head as a modular entity that comprises the central nervous system, including the brain, spinal cord, and craniofacial skeleton. An AnNA model was built using 39 anatomical nodes from the brain, spinal cord, and craniofacial skeleton. The linkages were identified using peripheral nerve supply and direct contact between structures. The Spinglass algorithm in the igraph software was applied to construct a network and identify the modules of the central nervous system-craniofacial skeleton anatomical network. Two modules were identified. These comprised an anterior module, which included the forebrain, anterior cranial base, and upper-middle face, and a posterior module, which included the midbrain, hindbrain, mandible, and posterior cranium. These findings may reflect the genetic and signaling networks that drive the mosaic central nervous system and craniofacial development and offer important systems biology perspectives for developmental disorders of craniofacial structures.

Quantitative Systems Pharmacology for Rare Disease Drug Development.

Though hundreds of drugs have been approved by the US Food and Drug Administration (FDA) for treating various rare diseases, most rare diseases still lack FDA-approved therapeutics. To identify the opportunities for developing therapies for these diseases, the challenges of demonstrating the efficacy and safety of a drug for treating a rare disease are highlighted herein. Quantitative systems pharmacology (QSP) has increasingly been used to inform drug development; our analysis of QSP submissions received by FDA showed that there were 121 submissions as of 2022, for informing rare disease drug development across development phases and therapeutic areas. Examples of published models for inborn errors of metabolism, non-malignant hematological disorders, and hematological malignancies were briefly reviewed to shed light on use of QSP in drug discovery and development for rare diseases. Advances in biomedical research and computational technologies can potentially enable QSP simulation of the natural history of a rare disease in the context of its clinical presentation and genetic heterogeneity. With this function, QSP may be used to conduct in-silico trials to overcome some of the challenges in rare disease drug development. QSP may play an increasingly important role in facilitating development of safe and effective drugs for treating rare diseases with unmet medical needs.

Double U-Net CycleGAN for 3D MR to CT image synthesis.

PURPOSE: CycleGAN and its variants are widely used in medical image synthesis, which can use unpaired data for medical image synthesis. The most commonly used method is to use a Generative Adversarial Network (GAN) model to process 2D slices and thereafter concatenate all of these slices to 3D medical images. Nevertheless, these methods always bring about spatial inconsistencies in contiguous slices. We offer a new model based on the CycleGAN to work out this problem, which can achieve high-quality conversion from magnetic resonance (MR) to computed tomography (CT) images. METHODS: To achieve spatial consistencies of 3D medical images and avoid the memory-heavy 3D convolutions, we reorganized the adjacent 3 slices into a 2.5D slice as the input image. Further, we propose a U-Net discriminator network to improve accuracy, which can perceive input objects locally and globally. Then, the model uses Content-Aware ReAssembly of Features (CARAFE) upsampling, which has a large field of view and content awareness takes the place of using a settled kernel for all samples. RESULTS: The mean absolute error (MAE), peak-signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM) for double U-Net CycleGAN generated 3D image synthesis are 74.56±10.02, 27.12±0.71 and 0.84±0.03, respectively. Our method achieves preferable results than state-of-the-art methods. CONCLUSION: The experiment results indicate our method can realize the conversion of MR to CT images using ill-sorted pair data, and achieves preferable results than state-of-the-art methods. Compared with 3D CycleGAN, it can synthesize better 3D CT images with less computation and memory.

Comprehensive Analysis of the Oncogenic Role of Targeting Protein for Xklp2 (TPX2) in Human Malignancies.

Mitosis and spindle assembly require the microtubule-associated protein Xenopus kinesin-like protein 2 (TPX2). Although TPX2 is highly expressed in several malignant tumor forms, little is known about its role in cancer. In this study, we performed the gene set enrichment analysis of TPX2 in 33 types of cancers and an extensive pan-cancer bioinformatic analysis using prognosis, tumor mutational burdens, microsatellite instability, tumor microenvironment, and immune cell infiltration data. According to the differential expression study, TPX2 was found to be overexpressed across all studied cancer types. Based on the survival analysis, increased TPX2 expression was associated with a poor prognosis for most cancers. The TPX2 expression level was confirmed to correlate with the clinical stage, microsatellite instability, and tumor mutational burden across all cancer types. Furthermore, TPX2 expression has been linked to tumor microenvironments and immune cell infiltration, particularly in bladder urothelial carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Finally, the gene set enrichment analysis implicated TPX2 in the regulation of aminoacyl tRNA biosynthesis, which is the most important tumor cell cycle signaling pathway. This comprehensive pan-cancer analysis shows that TPX2 is a prognostic molecular biomarker for most cancers and suggests its potential as an effective therapeutic target for the treatment of these diseases.

[Design and application of Baihui moxibustion box].

On the base of the principle of penetrating moxibustion and in combination with free adjustment devices such as movable U-shaped moxa stick holder and movable clamp, a new type of moxibustion box exerted on the head is designed, with precise positioning and sufficient heat intensity. Baihui moxibustion box is composed of two sections, i.e. body section and pillow section, which is as one structure. There are several vertical bar-shaped holes distributed evenly on the movable door outside moxa box. The U-shaped moxa stick holder on the inner side of the bar-shaped hole is connected with the fixed clamp on the outside, which is movable up and down, forward and backward for height adjustment. Such moxibustion box is characterized as accurate positioning, energy saving, temperature control and manpower saving.

[Comparison of apical root resorption of maxillary incisors between adolescents and adults after orthodontic treatment].

PURPOSE: To compare apical root resorption of maxillary incisors between adolescents and adults after orthodontic treatment. METHODS: Patients receiving orthodontic treatment in Affiliated Hospital of Chifeng University from May 2014 to August 2016 were enrolled, and divided into two age groups: adolescent group (32) and adult group (36). The included subjects received orthodontic fixed appliance treatment with straight-wire technique combined with Hawley type retainer for one year. After treatment, all patients were followed up for one year. Then the apical root resorption of maxillary incisors was evaluated by cone-beam CT (CBCT) at 4 time points, including pre-treatment (T1), end of treatment (T2), 6 months after treatment (T3), and 12 months after treatment (T4). Data were processed by SPSS 20.0 software package. RESULTS: The external root volume of maxillary central incisor, lateral incisors, mandibular central incisors and mandibular lateral incisors of both sides at T2-T4 was significantly lower than that at T1(P<0.05). There was partial increase in root volume of both groups at T3 and T4, while no significant difference from that at T2 (P>0.05). △root volume T3-T2 and △root volume T4-T3 had no significant difference between the two groups (P>0.05). △root volume T3-T2 in the adolescent group was significantly smaller than that in the adult group (P<0.05). Correlation analysis showed that the △root volumeT1-T2 was significantly positively correlated with age (P<0.05), meanwhile △root volume T3-T2 and △root volume T4-T3 were negatively correlated with age (P<0.05). CONCLUSIONS: Age is an important factor affecting the volume of root after orthodontic treatment. Adolescent patients with Class II division 1 malocclusion have a strong ability of self-healing after orthodontic treatment.

Integrated bioinformatic analysis identifies COL4A3, COL4A4, and KCNJ1 as key biomarkers in Wilms tumor.

Wilms tumor (WT) is one of the most common pediatric solid tumors, affecting 1 in 10,000 children, worldwide. A subset of WT patients has poor prognosis, which is associated with a high risk of advanced and/or recurrent disease. Therefore, candidate markers are urgently needed for the diagnosis and effective treatment of WT. We evaluated three mRNA microarray datasets to identify the differences between normal kidney tissue and WT tissue. Gene expression profiling revealed 130 differentially expressed genes (DEGs). Enrichment analysis and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the DEGs. Subsequently, we established a protein-protein interaction (PPI) network to reveal the associations among the DEGs and selected 10 hub genes, all of which were downregulated in WT. The expression of COL4A3, COL4A4, KCNJ1, MME, and SLC12A1 in WT tissues was significantly lower than that in normal renal tissues. Survival analyses using the Kaplan-Meier method showed that patients with WT and low expression of COL4A3, COL4A4, and KCNJ1 exhibited remarkably poor overall survival. The correlations among COL4A3, COL4A4, and KCNJ1 in WT were analyzed using cBioPortal; COL4A3, COL4A4, and KCNJ1 were positively correlated with each other. Thus, these genes were considered clinically significant and might therefore play important roles in carcinogenesis and the development of WT.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer.

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.

Benefit-Risk Summary of Nivolumab for the Treatment of Patients with Unresectable Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma After Prior Fluoropyrimidine- and Platinum-Based Chemotherapy.

On June 10, 2020, the U.S. Food and Drug Administration (FDA) approved nivolumab (OPDIVO; Bristol Myers Squibb, New York, NY) for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. Approval was based on the results of a single, randomized, active-control study (ATTRACTION-3) that randomized patients to receive nivolumab or investigator's choice of taxane chemotherapy (docetaxel or paclitaxel). The study demonstrated a significant improvement in overall survival (OS; hazard ratio = 0.77; 95% confidence interval: 0.62-0.96; p = .0189) with an estimated median OS of 10.9 months in the nivolumab arm compared with 8.4 months in the chemotherapy arm. Overall, fewer patients in the nivolumab arm experienced treatment-emergent adverse events (TEAEs) of any grade, grade 3-4 TEAEs, and serious adverse events compared with the control arm. The safety profile of nivolumab in patients with ESCC was generally similar to the known safety profile of nivolumab in other cancer types with the following exception: esophageal fistula was identified as a new, clinically significant risk in patients with ESCC treated with nivolumab. Additionally, the incidence of pneumonitis was higher in the ESCC population than in patients with other cancer types who are treated with nivolumab. This article summarizes the FDA review of the data supporting the approval of nivolumab for the treatment of ESCC. IMPLICATIONS FOR PRACTICE: The approval of nivolumab for the treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy was based on an overall survival (OS) benefit from a randomized, open-label, active-controlled study called ATTRACTION-3. Prior to this study, no drug or combination regimen had demonstrated an OS benefit in a randomized study for patients with ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma.

On May 29, 2020, the FDA approved atezolizumab for use in combination with bevacizumab, for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment. The approval was based on data from Study IMbrave150, which randomly allocated (2:1) patients to receive either atezolizumab plus bevacizumab (atezolizumab-bevacizumab) or sorafenib. Overall survival (OS) and independently assessed progression-free survival (PFS) in the intent-to-treat population were the primary endpoints. At the time of the primary analysis, the estimated median OS could not be estimated in the atezolizumab-bevacizumab arm and was 13.2 months in the sorafenib arm [HR, 0.58; 95% confidence interval (CI), 0.42-0.79]. The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) and 4.3 months (95% CI, 4.0-5.6) in the atezolizumab-bevacizumab and sorafenib arms, respectively. Adverse reactions occurring in >20% of patients receiving atezolizumab-bevacizumab were hypertension, fatigue/asthenia, and proteinuria. Adverse reactions occurring in >20% of patients receiving sorafenib were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Hemorrhage was reported more frequently in patients receiving atezolizumab-bevacizumab (25%) than in patients receiving sorafenib (17%). An evaluation for the presence of varices is recommended within 6 months of initiation of atezolizumab-bevacizumab in patients with HCC. Approval of atezolizumab-bevacizumab is likely to change the treatment paradigm for HCC, given that treatment with atezolizumab-bevacizumab resulted in improved OS and PFS compared with sorafenib, an accepted standard of care for first-line treatment of patients with unresectable HCC.See related commentary by Castet et al., p. 1827.

Comprehensive analysis of the functions and prognostic significance of RNA-binding proteins in bladder urothelial carcinoma.

Alterations in RNA-binding proteins (RBPs) are reported in various cancer types; however, the role of RBPs in bladder urothelial cancer (BLCA) remains unknown. This study aimed to systematically examine the function and prognostic significance of RBPs in bladder cancer using bioinformatics analyses. RNA sequencing and clinical data for BLCA were downloaded from The Cancer Genome Atlas (TCGA) database, and differentially expressed RBPs (DERBPs) between normal and cancer tissues were identified. A total of 388 DERBPs were identified, including 219 upregulated and 169 downregulated RBPs. All RBPs were screened for the prognostic model establishment and 9 RBPs (TRIM71, YTHDC1, DARS2, XPOT, ZNF106, FTO, IPO7, EFTUD2, and CTU1) were regarded as prognosis-related hub RBPs in BLCA. Further analysis revealed worse overall survival (OS) in the high-risk cohort compared to the model-based low-risk cohort. The area under the receiver operating characteristic (ROC) curve was 0.752 in the training group and 0.701 in the testing group, which supports the strength of its predictive ability. A nomogram was established according to nine prognosis-related RBPs, which showed strong predictive ability for BLCA. The C-indices of the nomogram were 0.7033 in the training group, and 0.6295 in the testing group. The prognosis-related hub RBPs may be involved in oncogenesis, development, and metastasis of BLCA. Our results will be of great significance in revealing the pathogenesis of BLCA, and developing new therapeutic targets and prognostic molecular markers for BLCA.

Development of a minimal physiologically-based pharmacokinetic/pharmacodynamic model to characterize target cell depletion and cytokine release for T cell-redirecting bispecific agents in humans.

T cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 µg/m2/day stepwise dosing regimen comparing to a 60 µg/m2/day flat dose in NHL patients. Furthermore, by only modifying the system parameters specific for ALL patients, the mPBPK/PD model successfully predicted the mitigation of IL-6 release by a blinatumomab 5-15 µg/m2/day stepwise dosing regimen comparing to a 15 µg/m2/day flat dose. Our work provided a case example to show how mPBPK/PD model can be used to support the discovery and clinical development of T cell-redirecting bsAbs.

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents.

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

Development and Translational Application of a Minimal Physiologically Based Pharmacokinetic Model for a Monoclonal Antibody against Interleukin 23 (IL-23) in IL-23-Induced Psoriasis-Like Mice.

The interleukin (IL)-23/Th17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 in both serum and lesional skin site. Furthermore, translational applications of the developed model were evaluated with incorporation of human PK for ustekinumab, an anti-human IL-23/IL-12 mAb developed for treatment of psoriasis, and human disease pathophysiology information in psoriatic patients. The results agreed well with the observed clinical data for ustekinumab. Our work provides an example on how mechanism-based PK/PD modeling can be applied during early drug discovery and how preclinical data can be used for human efficacious dose projection and guide decision making during early clinical development of therapeutic proteins.

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice.

We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.