Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.

Antibody-drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window.

Development of disulfide-stabilized Fabs for targeting of antibody-directed nanotherapeutics.

Antibody-directed nanotherapeutics (ADNs) represent a promising delivery platform for selective delivery of an encapsulated drug payload to the site of disease that improves the therapeutic index. Although both single-chain Fv (scFv) and Fab antibody fragments have been used for targeting, no platform approach applicable to any target has emerged. scFv can suffer from intrinsic instability, and the Fabs are challenging to use due to native disulfide over-reduction and resulting impurities at the end of the conjugation process.

An observational cohort study of pelvic floor photobiomodulation for treatment of chronic pelvic pain.

This research is the first to evaluate the effectiveness of -vaginal photobiomodulation therapy (TV-PBMT) for chronic pelvic pain. Observational analysis of 128 women, undergoing TV-PBMT for chronic pelvic pain. Minimal clinically important difference, defined as ≥2-point drop on a 0-10 numeric pain rating scale (NPRS), and effect size Cohen d coefficient, was calculated over nine treatments for overall pain, and pain with activities.

Peri- and Postoperative Outcomes of Outpatient vs Inpatient Laparoscopic Apical Prolapse Repair.

Study Objective: To assess the feasibility of outpatient laparoscopic management of apical pelvic organ prolapse along with indicated vaginal repairs and anti-incontinence procedures.

Design: Retrospective cohort study.

Setting: Tertiary-care academic center, Boston, MA.

Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to Increase Efficacy.

Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear.

Antibody-mediated targeting of TNFR2 activates CD8 T cells in mice and promotes antitumor immunity.

Tumor necrosis factor receptor 2 (TNFR2) is the alternate receptor for TNF and can mediate both pro- and anti-inflammatory activities of T cells. Although TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (T) in autoimmune diseases, the viability of TNFR2 as a target for cancer immunotherapy has been underappreciated. Here, we show that new murine monoclonal anti-TNFR2 antibodies yield robust antitumor activity and durable protective memory in multiple mouse cancer cell line models.

Sickle Cell Disease-Genetics, Pathophysiology, Clinical Presentation and Treatment.

Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the β-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the β-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention.

Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models.

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue.

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface.

Packed red cells versus whole blood transfusion for severe paediatric anaemia, pregnancy-related anaemia and obstetric bleeding: an analysis of clinical practice guidelines from sub-Saharan Africa and evidence underpinning recommendations.

Objective: Blood component transfusion is increasingly promoted in sub-Saharan Africa (SSA), but is resource-intensive so whole blood is often used. We examined SSA recommendations about whole blood and packed red cell transfusions for pregnancy-related bleeding or anaemia, and paediatric anaemia, and evaluated the evidence underpinning these recommendations.

Method: Relevant SSA guidelines were identified using five electronic databases, websites for SSA Ministries of Health, blood transfusion services and WHO.

Clinical practice guidelines in India: Quality appraisal and the use of evidence in their development.

Background: Guideline development in India has come under increased scrutiny with a growing interest in the use of evidence for guideline development.

Methods: Guidelines on the four leading causes of disability adjusted life years in India (ischemic heart disease, lower respiratory infections, chronic obstructive pulmonary diseases, tuberculosis), published on or after 2010 was searched in electronic databases and by other methods and their quality appraised by using the AGREE-II appraisal tool. In-depth, semistructured interviews were conducted with 15 individuals involved with the development of the included guidelines and the transcripts were analyzed using the framework approach.

Efficacy of FemiScan Pelvic Floor Therapy for the Treatment of Anal Incontinence.

Objectives: Pelvic floor muscle training can be effective in alleviating anal incontinence; however, women need instruction, motivation, and feedback to gain optimal benefit. The FemiScan Pelvic Floor Therapy System is approved in the United States and European Union for the treatment of urinary incontinence. It uses office electromyography and an in-home programmable device.

Novel HPLC-Based Screening Method to Assess Developability of Antibody-Like Molecules.

The discovery of antibodies that bind to targets with high affinity is now a routine exercise. However, it is still challenging to screen for candidates that, in addition to having excellent biological properties, also have optimal biophysical characteristics. Here, we describe a simple HPLC-based screening method to assess for developability factors earlier in the discovery process.

Improving the developability of an anti-EphA2 single-chain variable fragment for nanoparticle targeting.

Antibody-targeted nanoparticles have great promise as anti-cancer drugs; however, substantial developmental challenges of antibody modules prevent many candidates from reaching the clinic. Here, we describe a robust strategy for developing an EphA2-targeting antibody fragment for immunoliposomal drug delivery. A highly bioactive single-chain variable fragment (scFv) was engineered to overcome developmental liabilities, including low thermostability and weak binding to affinity purification resins.

Efficacy of FemiScan Pelvic Floor Therapy for the Treatment of Urinary Incontinence.

Objectives: Pelvic floor muscle training can be effective in alleviating urinary incontinence; however, women need instruction, motivation, and feedback to gain optimal benefit from pelvic rehabilitation. The Food and Drug Administration-approved FemiScan Pelvic Floor Therapy System uses office electromyography and an in-home programmable device to provide training, motivation, and feedback between office visits. This study was undertaken to document the outcomes of women who completed an MD-supervised program using the FemiScan Pelvic Floor Therapy System.

Surgical Outcomes of a Combined Surgical Approach for Apical Prolapse Repair.

Introduction We aimed to evaluate the safety, efficacy and surgical outcomes of combined laparoscopic/vaginal prolapse repair by two surgeons. Material and Methods A retrospective chart review of all patients (n = 135) who underwent apical prolapse repair from February 2009 to December 2012 performed in a collaborative manner by a Minimally Invasive Gynecologic Surgeon and a Urogynecologist. Demographic data (age, body mass index [BMI], race, gravidity, parity) and surgical information (estimated blood loss, operative time, intraoperative complications, readmission and reoperation rates, presence of postoperative infection) were collected.

Challenging immunosuppression treatment in lung transplant recipients with kidney failure.

Kidney failure after lung transplantation is a risk factor for chronic kidney disease. Calcineurin inhibitors are immunosuppressants which play a major role in terms of postoperative kidney failure after lung transplantation. We report our preliminary experience with the anti-interleukin-2 monoclonal antibody Basiliximab utilized as a "calcineurin inhibitor-free window" in the setting of early postoperative kidney failure after lung transplantation.

A novel screening method to assess developability of antibody-like molecules.

Monoclonal antibodies and antibody-like molecules represent a fast-growing class of bio-therapeutics that has rapidly transformed patient care in a variety of disease indications. The discovery of antibodies that bind to particular targets with high affinity is now a routine exercise and a variety of in vitro and in vivo techniques are available for this purpose. However, it is still challenging to identify antibodies that, in addition to having the desired biological effect, also express well, remain soluble at different pH levels, remain stable at high concentrations, can withstand high shear stress, and have minimal non-specific interactions.

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic.

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions.

Comprehensive optimization of a single-chain variable domain antibody fragment as a targeting ligand for a cytotoxic nanoparticle.

Antibody-targeted nanoparticles have the potential to significantly increase the therapeutic index of cytotoxic anti-cancer therapies by directing them to tumor cells. Using antibodies or their fragments requires careful engineering because multiple parameters, including affinity, internalization rate and stability, all need to be optimized. Here, we present a case study of the iterative engineering of a single chain variable fragment (scFv) for use as a targeting arm of a liposomal cytotoxic nanoparticle.

MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors.

Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target.

Rapid optimization and prototyping for therapeutic antibody-like molecules.

Multispecific antibody-like molecules have the potential to advance the standard-of-care in many human diseases. The design of therapeutic molecules in this class, however, has proven to be difficult and, despite significant successes in preclinical research, only one trivalent antibody, catumaxomab, has demonstrated clinical utility. The challenge originates from the complexity of the design space where multiple parameters such as affinity, avidity, effector functions, and pharmaceutical properties need to be engineered in concurrent fashion to achieve the desired therapeutic efficacy.

Controversies in utilization of transvaginal mesh.

Purpose Of Review: Due to technological advancements, transvaginal mesh use for prolapse and incontinence has exploded over the last decade with mixed results. Recent governmental guidelines have further increased the controversy regarding the risks and benefits of mesh use forcing clinicians to critically review the available data regarding transvaginal mesh use.

Recent Findings: With the success of the transvaginal tape procedure introduced in 1995 and re-popularization of the abdominal sacrocolpopexy using synthetic mesh, pelvic surgeons began to feel more comfortable using mesh in urogynecologic procedures and increasingly adopted the use of transvaginal mesh for repair of pelvic prolapse with the hopes of creating better long-term results with minimal complications.

Case report: a novel method for uterine-sparing hysteropexy.

Objective: The objective of this study was to describe a technique for uterine-sparing hysteropexy.

Case Report: A 50-year-old multiparous woman with pelvic organ prolapse underwent laparoscopic sacrohysteropexy utilizing polypropylene mesh with good clinical result.

Conclusions: Placement of mesh arms medial to the uterine vessels during a laparoscopic sacrohysteropexy can be facilitated by using blunt needles to introduce the mesh arms.