Sorting these libraries by FACS for binders against HER2/neu yielded antigen-specific
Fc binders (Fcab; Fc antigen binding) of which one was affinity matured, resulting in Fcab clone H10-03-6 which showed >10-fold improvement in antigen-binding activity versus Selleckchem GSK126 the parental clone. Pre-equilibrium surface plasmon resonance experiments revealed a K(D) value of 69 nM. H10-03-6 did not react with other members of the HER family and specifically interacted with HER2-positive but not with HER2-negative cells. Importantly, Fcab H10-03-6 elicited potent antibody-dependent cellular cytotoxicity in vitro. Finally, the in vivo half-life in mice was similar to wild-type Fc indicating that the amino acid changes in the CH3 domain did not affect the pharmacokinetic behavior
of the recombinant Fc. Our data demonstrate that the Fcab scaffold combines all features of normal antibodies in a small 50 kD homodimeric protein: antigen binding, effector functions and long half-life in vivo.”
“Introduction: N-(2-tert-butyl-14 (4,4-difluorocyclohexyl)methyl)-1 H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neurepathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure.
Methods: AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [C-11]pivalate
was obtained via C-11-carboxylation of tert-butyl lithium. The target compound, Pexidartinib solubility dmso [C-11]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [11C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-44(4,4-difluorocyclohexlmethylamino)phenylethanesulfonamide) selleck chemical in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey.
Results: The overall radiochemical yield of final formulated radiochemically pure (>99%) [C-11]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13 GBq/mu mol at time of administration (58 min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous.
Conclusions: AZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure. (C) 2013 Elsevier Inc. All rights reserved.”
“Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells.