Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody.

Fibroblast growth factor (FGF)21 improves insulin sensitivity, reduces body weight, and reverses hepatic steatosis in preclinical species. We generated long-acting FGF21 mimetics by site-specific conjugation of the protein to a scaffold antibody. Linking FGF21 through the C terminus decreased bioactivity, whereas bioactivity was maintained by linkage to selected internal positions.

Development of a long acting human growth hormone analog suitable for once a week dosing.

Human growth hormone was conjugated to a carrier aldolase antibody, using a novel linker by connecting a disulphide bond in growth hormone to a lysine-94 amine located on the Fab arm of the antibody. The resulting CovX body showed reduced affinity towards human growth hormone receptor, reduced cell-based activity, but improved pharmacodynamic properties. We have demonstrated that this CovX-body, given once a week, showed comparable activity as growth hormone given daily in an in vivo hypophysectomized rat model.

Development of novel linkers to conjugate pharmacophores to a carrier antibody.

We have developed modified maleimide novel linkers with improved chemical stability that could potentially be used in conjugating various pharmacophores such as oligo nucleotides, peptides, and proteins to antibodies to afford novel biologics with well-defined therapeutic benefits and improved pharmacokinetic properties. These linkers expand the array of tools available for bioconjugation of pharmacophores to antibodies.

Both AP-1 and NF-kappaB seem to be involved in tumour growth in an experimental rat hepatoma.

Daily treatment of rats bearing Yoshida AH-130 ascites hepatoma with the nuclear factor kappa-B (NF-kappaB) and activator protein-1 (AP-1) double inhibitors SP100030 and SP100207 at a dose of 5 mg/kg and 10 mg/kg of body weight, respectively, resulted in a clear inhibition of tumour growth. The decrease was not related to an altered cell cycle distribution of the tumour cell population suggesting a merely necrotic effect. The results presented confirm that both transcription factors are involved in the growth of the experimental tumour system used, suggesting that both signaling cascades play a very important role in the signaling of tumour cell proliferation.

Development of novel benzotriazines for drug discovery.

Background: The synthesis of novel benzotriazine heterocycles was developed independently around the same time by Bischler, Bamberger and Arndt. Over the years, different groups have reported the synthesis of benzotriazine based compounds.

Objective: This literature review gives an update on recent benzotriazine compounds and their applications.