Inhibitor specificity of amine oxidase

Although at the present time it appears clear that amine oxidase oxidation of adrenalin, or other o-diphenolic pressor amines such as were studied by Richter (6), does not play a significant physiological role, it is equally clear that the inactivation of aliphatic amines, phenethylamine and probably 4-hydroxyphenethylamine (tyramine), does predominantly take place by amine oxidase oxidation. In view of the evidence from the experiments of Ewins and Laidlaw (8) and a later study by Guggenheim and Löffler (9), such amine oxidations chiefly occur in the liver. In the present studies, an attempt was made to value quantitatively the inhibition of some of these particular type compounds by certain types of amines which are not themselves oxidized by the enzyme system (see Alles and Heegaard (10))

Substrate specificity of amine oxidase

The tyramine oxidase activity of liver extracts found by Hare (1), the aliphatic amine oxidase activity of brain, kidney, and liver extracts observed by Pugh and Quastel (2), and the adrenalin oxidase activity of similar extracts noted by Blaschko, Richter, and Schlossman (3) were brought under a common enzyme view-point by the latter authors. They were able to show (4) that extracts of brain, instestine, kindey, and liver from a number of mammals or representatives of the birds, reptiles, amphibians, and fishes all acted to absorb oxygen in the presence of several amine substrates. Hare (1) had shown that tyramine and phenethylamine form ammonia in the course of such oxidations, and Richter (5) showed that an ethylamino and a dimethylamino compound, as well as a number of methylamino and amino compounds, all yield the corresponding alkyl-amines or ammonia in the enzymic oxidation. The conslusion that the demonstrated variey of such enzymic activity can be acribed to the presence of a single type pf amine oxidase was dependent in large part on observations that the relative activities of a preparation from one source on a series of substrates bear some relation to the relative activities exhibited by a preparation from another source. Further evidence depended on the action of certain amines as inihibitors and apparent competition between substrates when two oxidizable substrates are present in the system. The degree to which relative activities of different enzyme preparations were constant in a series of substrates was not good in the data reported, and the fact that Hare (1) had not been able to note activity of the liver preparations she used upon adrenalin as the substrate appeared to require special explanations

KEYNOTE - D36: Personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 (ClinicalTrials.gov)