Year: 2016

Serum and colostral antibody production in cows immunized with recombinant human tumor necrosis factor.

The use of hyper-immune bovine colostrum as a human therapeutic platform is an emerging technology with potential to deliver the efficacy of antibody therapeutics with the convenience and safety of oral or topical application. It is necessary to understand how the bovine immune system responds to immunization with foreign proteins, both in terms of the serum antibody response and the transfer of antigen-specific antibodies into the colostrum to enable efficient large-scale production of therapeutic antibodies. We have immunized 25 cows with recombinant human tumor necrosis factor (rhTNF) and measured the levels of rhTNF-specific antibodies in the serum and colostrum of these animals. We observed a decline of 84 ± 9% in serum IgG1 concentrations in the final weeks of pregnancy that presumably reflects rapid transport of IgG1 into colostrum. The serum IgG2 levels remained constant, such that the serum IgG1 to IgG2 ratio was 1:20 at parturition. We observed substantial animal-to-animal variability in the levels of anti-rhTNF antibodies in both serum and colostrum samples. In particular, a subset of 4 cows had extraordinarily high colostral anti-rhTNF antibody production. Only a weak correlation was found between the peak serum anti-rhTNF activity and the colostral anti-rhTNF activity in these animals. The 4 cows with high colostral anti-rhTNF activities trended toward higher serum IgG1 loss relative to average colostral anti-rhTNF producers, but this difference was not statistically significant in this small sample. The high-anti-rhTNF-producing cows also exhibited a greater proportion of rhTNF-specific antibodies that bound to bovine IgG1- and IgG2-specific detection antibodies relative to the total anti-rhTNF immunoglobulin population. This finding suggests that the isotype distribution of the anti-rhTNF response is varied between individuals and genetic or environmental factors may increase the yield of antigen-specific colostral antibodies.
Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

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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.

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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.

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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.

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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]).

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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."