Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

Background: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).

Methods: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines.

Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses.

In solid tumours, the abundance of macrophages is typically associated with a poor prognosis. However, macrophage clusters in tumour-cell nests have been associated with survival in some tumour types. Here, by using tumour organoids comprising macrophages and cancer cells opsonized via a monoclonal antibody, we show that highly ordered clusters of macrophages cooperatively phagocytose cancer cells to suppress tumour growth.

Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

Purpose: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic.

Development and validation of a Level A in-vitro in-vivo correlation for tofacitinib modified-release tablets using extrudable core system osmotic delivery technology.

Purpose: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis.

Methods: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured.

Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion.

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion.

Nuclear rupture at sites of high curvature compromises retention of DNA repair factors.

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX.

Assessment of the Drug Interaction Potential of Ertugliflozin With Sitagliptin, Metformin, Glimepiride, or Simvastatin in Healthy Subjects.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of adults with type 2 diabetes mellitus, is expected to be coadministered with sitagliptin, metformin, glimepiride, and/or simvastatin. Four separate open-label, randomized, single-dose, crossover studies were conducted in healthy adults to assess the potential pharmacokinetic interactions between ertugliflozin 15 mg and sitagliptin 100 mg (n = 12), metformin 1000 mg (n = 18), glimepiride 1 mg (n = 18), or simvastatin 40 mg (n = 18). Noncompartmental pharmacokinetic parameters derived from plasma concentration-time data were analyzed using mixed-effects models to assess interactions.

Membrane fluctuations and acidosis regulate cooperative binding of 'marker of self' protein CD47 with the macrophage checkpoint receptor SIRPα.

Cell-cell interactions that result from membrane proteins binding weakly in can cause accumulations in that suggest cooperativity and thereby an acute sensitivity to environmental factors. The ubiquitous 'marker of self' protein CD47 binds weakly to SIRPα on macrophages, which leads to accumulation of SIRPα (also known as SHPS-1, CD172A and SIRPA) at phagocytic synapses and ultimately to inhibition of engulfment of 'self' cells - including cancer cells. We reconstituted this macrophage checkpoint with GFP-tagged CD47 on giant vesicles generated from plasma membranes and then imaged vesicles adhering to SIRPα immobilized on a surface.

Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study.

Aims: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842.

Methods: This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197).

Clinical experience with moroctocog alfa (AF-CC) in younger paediatric patients with severe haemophilia A: Two open-label studies.

Introduction: The pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF-CC) have been demonstrated in haemophilia A patients aged ≥6 years.

Aim: These studies aimed to further describe moroctocog alfa (AF-CC) experience in paediatric patients (<12 years) with severe haemophilia A (FVIII:C < 1%).

Methods: Two prospective, open-label studies enrolled patients aged <12 years: one study with 37 previously treated patients (PTPs) and another with 23 previously untreated patients (PUPs).

Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin.

Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (F ) of ertugliflozin. Eight healthy adult men received 100-μg i.

Filomicelles Deliver a Chemo-Differentiation Combination of Paclitaxel and Retinoic Acid That Durably Represses Carcinomas in Liver to Prolong Survival.

Drug resistance and relapse is common in cancer treatments with chemotherapeutics, and while drug combinations with naturally occurring, differentiation-inducing retinoic acid (RA) provide remission-free cures for one type of liquid tumor, solid tumors present major problems for delivery. Here, inspired by filoviruses that can be microns in length, flexible filomicelles that self-assemble from an amphiphilic block copolymer (PEG-PCL) are shown to effectively deliver RA and paclitaxel (TAX) to several solid tumor models, particularly in the liver. These hydrophobic compounds synergistically load into the cores of the elongated micelles, and the coloaded micelles prove most effective at causing cell death, ploidy, and durable regression of tumors compared to free drugs or to separately loaded drugs.

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.

Background: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA.

Methods: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015.

Genome variation across cancers scales with tissue stiffness - an invasion-mutation mechanism and implications for immune cell infiltration.

Many different types of soft and solid tumors have now been sequenced, and meta-analyses suggest that genomic variation across tumors scales with the stiffness of the tumors' tissues of origin. The opinion expressed here is based on a review of current genomics data, and it considers multiple 'mechanogenomics' mechanisms to potentially explain this scaling of mutation rate with tissue stiffness. Since stiff solid tissues have higher density of fibrous collagen matrix, which should decrease tissue porosity, cancer cell proliferation could be affected and so could invasion into stiff tissues as the nucleus is squeezed sufficiently to enhance DNA damage.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Domagrozumab (PF-06252616), an Antimyostatin Monoclonal Antibody, in Healthy Subjects.

Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in healthy subjects. A range of single ascending dose levels between 1 and 40 mg/kg IV and multiple doses (3 doses) of 10 mg/kg IV were tested (n = 8 per cohort). Additionally, a 3 mg/kg SC (n = 8) cohort also received domagrozumab.

SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors.

Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the "marker of self" CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted.

Engineering macrophages to eat cancer: from "marker of self" CD47 and phagocytosis to differentiation.

The ability of a macrophage to engulf and break down invading cells and other targets provides a first line of immune defense in nearly all tissues. This defining ability to "phagos" or devour can subsequently activate the entire immune system against foreign and diseased cells, and progress is now being made on a decades-old idea of directing macrophages to phagocytose specific targets, such as cancer cells. Engineered T cells provide precedence with recent clinical successes against liquid tumors, but solid tumors remain a challenge, and a handful of clinical trials seek to exploit the abundance of tumor-associated macrophages instead.

"Marker of Self" CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors.

Lentiviruses infect many cell types and are now widely used for gene delivery , but uptake of these foreign vectors by macrophages is a limitation. Lentivectors are produced here from packaging cells that overexpress "Marker of Self" CD47, which inhibits macrophage uptake of cells when prophagocytic factors are also displayed. Single particle analyses show "hCD47-Lenti" display properly oriented human-CD47 for interactions with the macrophage's inhibitory receptor SIRPA.

DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration.

Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1-a DNA repair protein. Here, constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic "comet" measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair.

Evaluation of the Effect of Tofacitinib on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Volunteers.

Tofacitinib is an oral Janus kinase inhibitor. Tofacitinib metabolism is primarily mediated by cytochrome P450 3A4. This phase 1 randomized, open-label, 2-way crossover study (NCT01137708) evaluated the effect of tofacitinib 30 mg twice daily on the single-dose pharmacokinetics of combination oral contraceptives ethinylestradiol (EE) and levonorgestrel (LN).

Single- and multiple-dose pharmacokinetics of tofacitinib in healthy Chinese volunteers.

Tofacitinib is an oral Janus kinase inhibitor. The objective of this phase 1, open-label study was to characterize the single- and multiple-dose pharmacokinetics (PK) of tofacitinib in 12 healthy, adult Chinese volunteers. Eligible subjects received oral tofacitinib 10 mg once daily on days 1 and 6 and twice daily on days 2-5.

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

Background: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers.

Objectives: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum).

Methods: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals.

Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific 'Marker of Self' CD47, and target physical properties.

Professional phagocytes of the mononuclear phagocyte system (MPS), especially ubiquitous macrophages, are commonly thought to engulf or not a target based strictly on 'eat me' molecules such as Antibodies. The target might be a viable 'self' cell or a drug-delivering nanoparticle, or it might be a cancer cell or a microbe. 'Marker of Self' CD47 signals into a macrophage to inhibit the acto-myosin cytoskeleton that makes engulfment efficient.