This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures.

It is disclosed a method for determining the biological activity of defibrotide, which comprises the steps of: a) bringing into contact defibrotide, mammalian euglobulin and a substrate specific for the plasmin which, by reaction with the plasmin, provides a measurable product; and b) measuring the amount of product formed at successive times, to thereby determine the biological activity of the defibrotide. Liquid defibrotide formulations are also disclosed, preferably water solutions, having a defined biological activity and, in particular, having an activity of 25 to 35 IU/mg of defibrotide, preferably from 27.5 to 32.5 IU/mg and, more preferably, from 28 to 32 IU/mg.

The present invention provides a fibrinolytic composition useful as a therapeutic for administration to a patient having a thrombotic occlusion. In one aspect of the present invention, the fibrinolytic composition comprises a reversibly inactivated acidified serine protease substantially free of a plasminogen activator, a low buffering capacity buffer, and optionally, a stabilizing agent. In another aspect of the invention, the fibrinolytic composition of the present invention comprises a reversibly inactivated acidified plasmin substantially free of a plasminogen activator, a low buffering capacity buffer, and optionally, a stabilizing agent.

The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules.

This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures.

The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules.

The present invention discloses modified forms of plasmin with advantageous properties. As compared to their natural unmodified form, these variants exhibit significantly modulated kinetics in terms of delayed inhibition characteristics in the presence of specific inhibitors, such as .sub.2-antiplasmin (.sub.2-AP). These include PEG-conjugated thiol derivatives of truncated plasmin with potential clinical applications in various regimens of thrombolytic therapies.

The invention relates to variants of plasminogen and plasmin comprising one or more point mutations in the catalytic domain which reduce or prevent autocatalytic destruction of the protease activity of plasmin. Compositions, uses and methods of using said variants of plasminogen and plasmin are also disclosed.

This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures.

Compounds for the prevention and treatment of cancer have a first binding peptide from a urokinase-type plasminogen receptor (uPAR) antagonist operatively linked to an antibody peptide operatively linked to a second binding peptide from an endostatin or plasminogen derived peptide sequence.