Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma.

Unlabelled: MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design.

Metabolism of an Oxime-Linked Antibody Drug Conjugate, AGS62P1, and Characterization of Its Identified Metabolite.

AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time.

Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models.

The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4.

In vivo ocular pharmacokinetics of acyclovir dipeptide ester prodrugs by microdialysis in rabbits.

In vivo corneal absorption of the dipeptide prodrugs of acyclovir (ACV) was evaluated using microdialysis in rabbits. A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microliters of a 1% solution of L-valine-ACV (VACV), glycine-valine-ACV (GVACV), valine-valine-ACV (VVACV), and valine-tyrosine-ACV (VYACV) was placed in the corneal well and was allowed to diffuse for a period of 2 h, following which the drug solution was aspirated and well removed.

Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers.

Purpose: TRX1 is a nondepleting anti-CD4 monoclonal IgG1 antibody being developed to induce tolerance by blocking CD4-mediated functions. The purpose of this study is to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of TRX1 and to develop a receptor-mediated PK/PD model that characterizes the relationships between serum TRX1 concentration and total and free CD4 expression in healthy male volunteers.

Methods: Nine subjects from three dosing cohorts in double-blinded, placebo-controlled phase I clinical study was included in the analysis.

Role of efflux pumps and metabolising enzymes in drug delivery.

The impact of efflux pumps and metabolic enzymes on the therapeutic activity of various drugs has been well established. The presence of efflux pumps on various tissues and tumours has been shown to regulate the intracellular concentration needed to achieve therapeutic activity. The notable members of efflux proteins include P-glycoprotein, multi-drug resistance protein and breast cancer resistance protein.

Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium.

Purpose: The aim of this study was to explore the feasibility of improvement of ocular bioavailability of the antiviral agent acyclovir by designing amino acid prodrugs targeted to the amino acid transporters on the rabbit cornea.

Materials And Methods: Transcorneal flux of two water-soluble amino acid ester prodrugs of acyclovir (ACV), gamma-glutamate-ACV (EACV) and L-tyrosine-ACV (YACV), was studied across freshly excised rabbit cornea. Chemical and enzymatic hydrolysis studies of the two prodrugs were also conducted.

Validation of an ocular microdialysis technique in rabbits with permanently implanted vitreous probes: systemic and intravitreal pharmacokinetics of fluorescein.

The purpose of this work is to validate a novel ocular microdialysis sampling technique in rabbits with permanently implanted vitreous probes. This objective is achieved by studying the vitreous pharmacokinetics of fluorescein following systemic and intravitreal administration. The rabbits were divided into two groups (groups I and II) based on whether or not they were allowed a recovery period following surgical implantation of probes.

Pharmacokinetics of novel dipeptide ester prodrugs of acyclovir after oral administration: intestinal absorption and liver metabolism.

The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV), is an effective antiherpetic drug. Systemic availability of ACV in humans is 3 to 5 times higher after oral administration of VACV. Enhanced bioavailability of VACV has been attributed to its carrier-mediated intestinal absorption via hPEPT1 peptide transporter followed by rapid and complete conversion to ACV.

Mechanism of a model dipeptide transport across blood-ocular barriers following systemic administration.

The purposes of this study were to provide functional evidence for the presence of a peptide transporter on blood-ocular barriers and to elucidate the mechanism of a dipeptide transport across these barriers following systemic administration. Glycylsarcosine was chosen as a model dipeptide and [(3)H] glycylsarcosine was administered through the marginal ear vein of New Zealand white rabbits. At the end of an experimental period, vitreous humor, retina and aqueous humor were collected.

Molecular evidence and functional expression of P-glycoprotein (MDR1) in human and rabbit cornea and corneal epithelial cell lines.

Purpose: Efflux pumps such as P-glycoprotein (P-gp; MDR1) are believed to be a major barrier to drug delivery. The purpose of this work was to determine whether cornea and corneal epithelial cells expresses the functionally active P-gp efflux pump.

Method: Cultured rabbit primary corneal epithelial cells (rPCECs) and a corneal cell line (Statens Seruminstitut rabbit cornea [SIRC] cells) were selected as the model.

In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model.

Purpose: A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis.

Methods: The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 microL of 10(5) plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 microL of 10(5) PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group.

Transporters/receptors in the anterior chamber: pathways to explore ocular drug delivery strategies.

Membrane transporters/receptors are involved in drug transport processes and play a key role in intestinal absorption, tissue distribution and elimination. Drug targeting to specific transporters and receptors using carrier-mediated absorption has immense clinical significance. Ocular drug delivery is a challenging task since it involves drug transport across various barriers in the eye.

Interactions of the dipeptide ester prodrugs of acyclovir with the intestinal oligopeptide transporter: competitive inhibition of glycylsarcosine transport in human intestinal cell line-Caco-2.

The oligopeptide transporter may be exploited to enhance the absorption of drugs by synthesizing their dipeptide ester prodrugs, which may be recognized as its substrates. Various dipeptide esters of acyclovir (ACV), an antiviral nucleoside analog, were synthesized. Enzymatic hydrolysis and affinity of the prodrugs toward the human intestinal peptide transporter hPEPT1 were studied using the human intestinal Caco-2 cell line.

Mechanism of corneal permeation of L-valyl ester of acyclovir: targeting the oligopeptide transporter on the rabbit cornea.

Purpose: To delineate mechanisms associated with the corneal transport of a L-valine prodrug of an antiviral agent, acyclovir.

Method: The permeability and enzymatic hydrolysis of L-Val-ACV were evaluated using freshly excised rabbit cornea. Transport mechanism across rabbit cornea was investigated through a competitive inhibition study of L-Val-ACV with other substrates of human peptide transporter (hPepT1).

Current prodrug strategies via membrane transporters/receptors.

Prodrug design strategies have been employed to improve the delivery of drugs with undesirable pharmacokinetic properties such as chemical stability and lack of specificity. Targeted prodrug design represents a new strategy for site-directed and efficient drug delivery. Targeting of drugs to transporters and receptors to aid in site-specific carrier-mediated absorption is emerging as a novel and clinically significant approach.

Effect of mono- and di-acylation on the ocular disposition of ganciclovir: physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs.

A series of short-chain carboxylic mono- and diesters of ganciclovir were synthesized in our laboratory. Physico-chemical properties, i.e.