Efficient Generation of Stable Bispecific IgG1 by Controlled Fab-Arm Exchange.

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.

Proc Natl Acad Sci U S A. 2013 Mar 11;
Labrijn AF, Meesters JI, de Goeij BE, van den Bremer ET, Neijssen J, van Kampen MD, Strumane K, Verploegen S, Kundu A, Gramer MJ, van Berkel PH, van de Winkel JG, Schuurman J, Parren PW

The promise of bispecific antibodies (bsAbs) to yield more effective therapeutics is well recognized; however, the generation of bsAbs in a practical and cost-effective manner has been a formidable challenge. Here we present a technology for the efficient generation of bsAbs with normal IgG structures that is amenable to both antibody drug discovery and development. The process involves separate expression of two parental antibodies, each containing single matched point mutations in the CH3 domains. The parental antibodies are mixed and subjected to controlled reducing conditions in vitro that separate the antibodies into HL half-molecules and allow reassembly and reoxidation to form highly pure bsAbs. The technology is compatible with standard large-scale antibody manufacturing and ensures bsAbs with Fc-mediated effector functions and in vivo stability typical of IgG1 antibodies. Proof-of-concept studies with HER2×CD3 (T-cell recruitment) and HER2×HER2 (dual epitope targeting) bsAbs demonstrate superior in vivo activity compared with parental antibody pairs. HubMed – drug

Anti-HER3 Domain 1 and 3 Antibodies Reduce Tumor Growth by Hindering HER2/HER3 Dimerization and AKT-Induced MDM2, XIAP, and FoxO1 Phosphorylation.

Neoplasia. 2013 Mar; 15(3): 335-47
Lazrek Y, Dubreuil O, Garambois V, Gaborit N, Larbouret C, Le Clorennec C, Thomas G, Leconet W, Jarlier M, Pugnière M, Vié N, Robert B, Monnet C, Bouayadi K, Kharrat H, Mondon P, Pèlegrin A, Chardès T

Blockade of the human epidermal growth factor receptor 3 (HER3) and of the downstream phosphatidylinositide 3-kinase (PI3K)/AKT pathway is a prerequisite for overcoming drug resistance and to develop novel treatments for cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2 cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers. HubMed – drug

Myeloprotection by cytidine deaminase gene transfer in antileukemic therapy.

Neoplasia. 2013 Mar; 15(3): 239-48
Lachmann N, Brennig S, Phaltane R, Flasshove M, Dilloo D, Moritz T

Gene transfer of drug resistance () genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has been proven by overexpression of a mutant -methylguaninemethyltransferase in the hematopoietic system of glioblastoma patients treated with temozolomide. Given its protection capacity against such relevant drugs as cytosine arabinoside (ara-C), gemcitabine, decitabine, or azacytidine and the highly hematopoiesis-specific toxicity profile of several of these agents, cytidine deaminase (CDD) represents another interesting candidate gene and our group recently has established the myeloprotective capacity of gene transfer in a number of murine transplant studies. Clinically, CDD overexpression appears particularly suited to optimize treatment strategies for acute leukemias and myelodysplasias given the efficacy of ara-C (and to a lesser degree decitabine and azacytidine) in these disease entities. This article will review the current state of the art with regard to gene transfer and point out potential scenarios for a clinical application of this strategy. In addition, risks and potential side effects associated with this approach as well as strategies to overcome these problems will be highlighted. HubMed – drug

What is the evidence for chronic concussion-related changes in retired athletes: behavioural, pathological and clinical outcomes?

Br J Sports Med. 2013 Apr; 47(5): 327-30
McCrory P, Meeuwisse WH, Kutcher JS, Jordan BD, Gardner A

The purpose of this paper was to review the current state of evidence for chronic traumatic encephalopathy (CTE) in retired athletes and to consider the potential differential diagnoses that require consideration when retired athletes present with cognitive and psychiatric problems.MEDLINE, CINAHL, EMBASE, Mosby’s Index, PsycEXTRA, PsycINFO and Scopus. Key words included CTE, dementia pugilistica, punch drunk syndrome, traumatic encephalopathy, CTE, repetitive head injury, sports concussion, multiple concussions, chronic concussions, subconcussive blow and sports-related traumatic brain injury.At present, there are no published epidemiological, cross-sectional or prospective studies relating to modern CTE. Owing to the nature of the published studies, being case reports or pathological case series, it is not possible to determine the causality or risk factors with any certainty. As such, the speculation that repeated concussion or subconcussive impacts cause CTE remains unproven. The extent to which age-related changes, psychiatric or mental health illness, alcohol/drug use or coexisting dementing illnesses contribute to this process is largely unaccounted for in the published literature.At present, the interpretation of causation in the modern CTE case studies should proceed cautiously. The causal assumptions require further prospective or longitudinal studies on the topic. HubMed – drug