Monoclonal antibodies (mAbs) continue to reign supreme, although cellular and gene therapies are slowly starting to gather momentum. Burgeoning growth in biosimilars may threaten future brand monopolies for mAbs and other biologics.

/pdf/biopharmaceutical-benchmarks-2018-2a2flzlvwf.pdf

Biopharmaceutical benchmarks 2018.

Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.

/pdf/mechanisms-of-resistance-to-aminoglycoside-antibiotics-42yjz8z4eg.pdf

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3+ T cells.

/pdf/nano-enabled-pancreas-cancer-immunotherapy-using-immunogenic-ljx50mg8xo.pdf

Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression

https://cyberleninka.org/article/n/144647.pdf

New agents for the treatment of drug-resistant Mycobacterium tuberculosis

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

https://science.sciencemag.org/content/sci/348/6239/1106.full.pdf

Targeting DnaN for tuberculosis therapy using novel griselimycins

Development of bispecific antibodies (BsAbs) as therapeutic agents has recently attracted significant attention, and investments in this modality have been steadily increasing. This review discusses challenges, and suggestions to overcome them, associated with the development of BsAbs, specifically those pertaining to clinical pharmacology, pharmacometrics, and bioanalysis. These challenges and possible solutions are discussed by presenting several case studies of BsAbs that have gained regulatory approval or that are currently in clinical development.

BsAbs, also termed “dual‐targeting” or “dual‐specificity” antibodies, have the ability to bind two different targets on the same or different cell(s); the targets may be cell‐surface receptors or soluble ligands, as shown in Figure ​1.1. These dual‐nature antibodies have key advantages that can potentially enhance therapeutic efficacy compared with monotherapy or traditional combination therapies by: i) simultaneously blocking two different targets or mediators that have a primary role in the disease pathogenesis; ii) inducing cell signaling pathways (e.g., proliferation or inflammation); iii) retargeting to mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC); iv) avoiding the development of resistance and increasing antiproliferative effects, specifically in oncology; and v) temporarily engaging a patient's own cytotoxic T cells to target cancer cells, thus activating cytotoxic T cells to cause tumor lysis (e.g., bispecific T‐cell engagers (BiTE)).




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Figure 1


Various designs for BsAb molecules (a) Dimers inhibition: BsAbs can bind to two receptors/targets (HER2/HER3, HER2/HER4) on the same cell (e.g., MM‐111); (b) Dual inhibition: BsAbs can inhibit two different cytokines simultaneously, for example, COVA322 that inhibits TNF‐α and IL17A; (c) Triomabs: The antigen binding site binds to target cell receptors (EpCAM, HER2, or CD20) and the T‐cell receptors (CD3). The heavy chain site binds to NK cells or dendritic cells or macrophages/phagosome (e.g., catumaxomab, ertumaxomab, FBTA05); (d) Two‐ligand inactivation: two arms bind to different ligands on different cells belonging to the same population, such as DLL4 x VEGF, TNF‐α x IL17A, IL4 x IL13 (e.g., OMP‐305B83, COVA322, SAR156597); (e) Transmembrane/transcytosis: The BsAbs are designed specifically to cross the barriers/membrane via receptor transport (transferrin receptor) and bind to enzymes/receptors (BACE1) on the other side; (f) BiTE antibody construct: These are designed to bridge T cells and target cells by binding to CD3/CD28 or CD19/CD20/CD22/CEA/EpCAM, respectively (e.g., blinatumomab, MEDI‐565, MT110). The examples mentioned above can be found in Table 2 for further information. BACE1, β‐secretase 1; BiTE, bispecific T‐cell engagers; BsAbs, bispecific antibodies; DDL4, delta‐like ligand 4; EpCAM, epithelial cell adhesion molecule; HER, human epidermal growth factor receptor; IL, interleukin; NK, Natural Killer; TNF‐α, tumor necrosis factor‐alpha; VEGF, vascular endothelial growth factor.

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12459

Clinical Pharmacology and Translational Aspects of Bispecific Antibodies.

Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties

Drug Discovery and Development - New Advances

We conducted a comprehensive analysis of clinical pharmacology evaluations in initial submissions of 56 oncology new molecular entities approved by the US Food and Drug Administration between January 2011 and April 2017. Results from studies evaluating food effect, QTc prolongation, drug-drug interactions, renal and hepatic impairment effects, and dose optimization, as well as postmarketing requirements/commitments, were reviewed. This reverse translational research highlights the importance of clinical pharmacology and pharmacometrics in benefit-risk characterization, regulatory review, and labeling of anticancer therapeutics.

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12527

Reverse Translation of US Food and Drug Administration Reviews of Oncology New Molecular Entities Approved in 2011–2017: Lessons Learned for Anticancer Drug Development

With the increased emergence of anti-infective resistance in recent years, much focus has recently been drawn to the development of new anti-infectives and the optimization of treatment regimens and combination therapies for established antimicrobials. In this context, the field of pharmacometrics using quantitative numerical modeling and simulation techniques has in recent years emerged as an invaluable tool in the pharmaceutical industry, academia and regulatory agencies to facilitate the integration of preclinical and clinical development data and to provide a scientifically based framework for rational dosage regimen design and treatment optimization. This review highlights the usefulness of pharmacometric analyses in anti-infective drug development and applied pharmacotherapy with select examples.

Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives.

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