Author: [email protected]

Tetravalent anti-CD20/CD3 bispecific antibody for the treatment of B cell lymphoma.

Bispecific antibodies (bsAbs) are second generation antibodies for therapeutic application in immunotherapy. One of the major strategies of the bsAb platform is the recruitment of immune effector T cells by incorporating an anti-CD3 domain. A bispecfic T-cell engager (BiTE), with one end having an affinity for CD3 and the other end with affinity for CD19, has been approved in the US and Europe for the treatment of acute lymphoblastic leukemia. However, due to their small size and lack of Fc region, these single-chain variable fragment (scFv) bsAbs have short half-lives in vivo. Additionally, poor solubility, structural instability, and low production yields have also become major challenges in the bulk production process. To overcome these challenges, we have engineered a tetravalent bsAb with bivalent binding specificity for the CD20 and CD3 antigen in an immunoglobulin G (IgG) format. The fusion of the anti-CD3 scFvs to the CD20 antibody via a linker-hinge domain (LHD) results in improved antibody stabilization and properties. Here we demonstrate this antibody’s highly efficient cancer cell elimination in a dose-dependent manner in a CD20-expressing B lymphoblastoid cell line in vitro. Our data suggest the potential clinical application of this bsAb for the treatment of CD20-expressing B cell malignancies.
Copyright © 2016. Published by Elsevier Inc.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!


Targeting Coagulation Factor XII as a Novel Therapeutic Option in Brain Trauma.

Traumatic brain injury is a global major public health problem for which specific therapeutic interventions are lacking. There is therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in two mouse models of traumatic brain injury.
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. This article is protected by copyright. All rights reserved.
© 2016 American Neurological Association.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!


The Reg3α (HIP/PAP) Lectin Suppresses Extracellular Oxidative Stress in a Murine Model of Acute Liver Failure.

Acute liver failure (ALF) is a rapidly progressive heterogeneous illness with high mortality rate and no widely accessible cure. A promising drug candidate according to previous preclinical studies is the Reg3α (or HIP/PAP) lectin, which alleviates ALF through its free-radical scavenging activity. Here we study the therapeutic targets of Reg3α in order to gain information on the nature of the oxidative stress associated with ALF.
Primary hepatocytes stressed with the reactive oxygen species (ROS) inducers TNFα and H2O2 were incubated with a recombinant Reg3α protein. ALF was induced in C57BL/6J mice by an anti-CD95 antibody. Livers and primary hepatocytes were harvested for deoxycholate separation of cellular and extracellular fractions, immunostaining, immunoprecipitation and malondialdehyde assays. Fibrin deposition was studied by immunofluorescence in frozen liver explants from patients with ALF.
Fibrin deposition occurs during experimental and clinical acute liver injuries. Reg3α bound the resulting transient fibrin network, accumulated in the inflammatory extracellular matrix (ECM), greatly reduced extracellular ROS levels, and improved cell viability. Hepatocyte treatment with ligands of death receptors, e.g. TNFα and Fas, resulted in a twofold increase of malondialdehyde (MDA) level in the deoxycholate-insoluble fractions. Reg3α treatment maintained MDA at a level similar to control cells and thereby increased hepatocyte survival by 35%. No antioxidant effect of Reg3α was noted in the deoxycholate-soluble fractions. Preventing fibrin network formation with heparin suppressed the prosurvival effect of Reg3α.
Reg3α is an ECM-targeted ROS scavenger that binds the fibrin scaffold resulting from hepatocyte death during ALF. ECM alteration is an important pathogenic factor of ALF and a relevant target for pharmacotherapy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!


Oasmia Pharmaceutical Reports Positive Clinical Study Results for Proprietary XR17 Nanotechnology

On April 05, 2016 Oasmia Pharmaceutical AB (NASDAQ: OASM), a developer of a new generation of drugs within human and veterinary oncology, reported the results of a study in healthy volunteers for the Company’s XR17 nanotechnology that it believes indicates the excipient’s vast potential across many pharmaceutical indications beyond the cytostatic drug market (Press release, Oasmia, APR 5, 2016, View Source [SID:1234510423]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Company recently completed a single center, randomized, single-blind, placebo-controlled study to assess the pharmacokinetics, safety and tolerability of XR17 and XMeNa, one of the components of XR17, after performing single ascending doses in 48 healthy subjects. XR17 has been used in several previously conducted clinical trials without any adverse events connected to the substance, a result that now has been confirmed and reinforced by this study.

XR17 is Oasmia’s proprietary excipient, transforming novel or existing un-soluble molecules into water soluble nanoparticle formations which instantly is released in the blood stream without added solvent, resulting in shorter infusion time and no pre-medication for the patient. This innovative approach also allows for multiple cytostatics to be given in a single infusion, as opposed to a traditional process that would usually require two or more infusions. XR17 is the excipient of Oasmia’s human oncology treatment compound Paclical, as well as Oasmia’s formulation of doxorubicin for veterinary use, Doxophos Vet and Paccal Vet.

Oasmia believes this clinical breakthrough presents a tremendous opportunity to create revenue streams in addition to the development and commercial sales of its human and animal oncology treatments. The confirmation of XR17 as a drug delivery system creates the potential for licensing and deployment opportunities in additional therapeutics outside of the oncology treatment sector. A 2014 report estimated that "70% of molecules in the developmental pipeline are believed to be poorly soluble and 40% of already approved drugs are poorly soluble," creating what Oasmia believes is a market opportunity that can be fulfilled by XR17.

"The drug discovery program is often limited by poor solubility that in many cases can exclude the patients from highly potent medications and result in additional and expensive administrations. In worst cases, drugs that have shown strong potential in animal models may not be used as a pharmaceutical treatment due to solubility problems," said Margareta Eriksson, Vice President of Clinical Development at Oasmia Pharmaceutical. "We are pleased that this clinical study yielded the results we had anticipated, and consider it the first step in positioning XR17 as a drug delivery system with expansive potential in the pharmaceutical industry."

"The results of this clinical study present a tremendous market opportunity for Oasmia, one that we seek to capitalize on for future revenue potential," said Julian Aleksov, Executive Chairman of Oasmia. "XR17 has thus far fulfilled our expectations, clearly demonstrating that its potential for widespread adoption by the pharmaceutical sector is no longer exclusive to oncology, but all treatments. We believe this breakthrough and subsequent development will create a revenue channel for Oasmia in addition to the sales efforts of our family of commercialized and next-generation oncology products."

Regeneron and MedImmune Enter into Licensing Agreement for the Development of Antibody Drug Conjugates to Treat Cancer

On April 5, 2016 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and MedImmune, the global biologics research and development arm of AstraZeneca (LSE: AZN, SSE: AZN, NYSE: AZN), reported that they have entered into a licensing agreement under which Regeneron will use MedImmune’s pyrrolobenzodiazepine (PBD)-based warhead and linker technology to produce antibodydrug conjugates (ADCs) as potential cancer treatments (Press release, Regeneron, APR 5, 2016, View Source [SID:1234510419]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Regeneron will have exclusive rights to utilize MedImmune’s proprietary PBD technology to develop ADCs against a number of cancer targets. MedImmune will receive an upfront payment, development and commercial milestone payments, as well as single-digit royalties on net sales of such products. MedImmune has the option to develop and commercialize certain products created with this technology in territories outside of the United States.

"Developing next generation antibody-drug conjugates, including our proprietary PBD technology, is one of our key strategic platforms in advancing cancer therapies. Today’s collaboration represents our third partnership in this area, as we look to grow our ADC portfolio both internally and externally," said Ronald Herbst, Vice President, Oncology Research & Development, MedImmune. "We are pleased to be working with Regeneron, a company that is committed to advancing scientific innovation in cancer treatments. Regeneron’s research capabilities complements our commitment to discovering and developing the next generation of cancer therapies."

ADCs are a promising area of cancer drug technology which may help enable the selective killing of cancer cells by combining a cytotoxic agent, or "warhead", with specific cancertargeting antibodies. MedImmune is committed to advancing its pre-clinical and clinical stage ADC portfolio, in addition to its focus in immuno-oncology.

"We believe the most successful approaches to cancer R&D will combine multiple innovative therapies and technologies, and therefore we are pursuing a diverse array of strategies, pathways and modalities including ADCs, bispecific antibodies and monocolonal antibodies," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "This new agreement will further bolster our efforts to advance new, effective treatment options for cancer patients in need."

Regeneron’s clinical pipeline in oncology includes a PD-1 checkpoint inhibitor antibody, which is being developed in collaboration with Sanofi, and a CD20xCD3 bispecific antibody. Regeneron expects to advance multiple additional candidates into human clinical trials over the next 12 to 24 months.

MedImmune’s PBD technology was invented and developed by Spirogen, a company acquired by MedImmune in 2013.