Enzon, Inc.

Cryolife, Inc.

Other

The United States of America As Represented by the Department of Health

Carl W Gilbert

Robert G Shorr

Kirby S Black

Eleanor B McGowan

Myung-Ok Cho

T Gregory P Harper

Richard B Greenwald

Brian M Martin

Edward J Ginns

Terrence W Hallahan

Myung-ok Park-Cho

Energy-reversible acyl conjugates, intermediates, and related compositions are disclosed. In preferred aspects, examples of such compositions include: 

Bifunctional energy-reversible acyl-compositions

A prodrug composition containing a cinnamate moiety and a biologically active molecule moiety which can be released by hydrolysis or activated by light is disclosed. The cinnamate moiety can have substituents of various electronically donating or electronically withdrawing groups to modify the cinnamate moiety's electric properties as well as photo reactivities for the purpose of achieving a proper hydrolysis rate of the acyl bond between the biologically active molecule moiety and the cinnamic acid backbone. The biologically active molecule can be any biologically active agent or diagnostic, for example, a chemotherapeutic such as a paclitaxel, campotothecin, doxorubicin, amethopterin, etoposide, or fluconazole. The prodrug composition can be modified to add a carrier moiety on the prodrug composition for targeting or to facilitate uptake of the drug. The prodrug compositions can be activated with an energy source to release the drug at the desired site. Representative energy sources can be in the form of electric force, ultrasound, light or radiation of a radioactive material which can be administered either externally or internally.

Prodrugs via acylation with cinnamate

Compositions containing alpha interferon conjugated to a substantially non-antigenic polymer are disclosed in which at least about 30% of the conjugates include covalent attachment of the alpha interferon to the substantially non-antigenic polymer at a histidine. Also disclosed is a process for preparing the conjugates. The process includes contacting an alpha interferon with a succinimidyl carbonate-activated substantially non-antigenic polymer at a pH which is sufficient to facilitate covalent attachment of the polymer on a histidine of the alpha interferon.

Interferon polymer conjugates

A process for preparing .alpha.-interferon-polymer conjugates having high levels of retained interferon activity and relatively long circulating lives in vivo is disclosed. The process includes forming substantially non-antigenic .alpha.-interferon-polymer conjugates, combining the .alpha.-interferon-polymer conjugates with a sufficient amount of an acid to reduce the pH of the conjugates to a level which is sufficient to cleave the polymer linkages in an active site area of the interferon and thereafter adjusting the .alpha.-interferon-polymer conjugates to a physiologically-acceptable pH. Methods of treating interferon-susceptible conditions with the compositions of the present invention are also disclosed.

.alpha.-interferon-polymer-conjugates having enhanced biological

Conjugates containing a substance with coagulant activity, such as recombinant Factor IX, non-antigenic polymers, such as poly(ethylene glycol), are disclosed. Also disclosed are methods of forming the novel conjugates of this invention.

Factor IX -- polymeric conjugates

Interferon-polymer conjugate containing compositions having high levels of retained interferon activity and relatively long circulating lives in vivo are disclosed. The compositions contain a mixture of mono-interferon-polymer conjugates and bis-interferon-polymer conjugates, with both species containing substantially a single polymer strand. The conjugate compositions are prepared by reacting about 1 mole of an interferon with from about 0.125 to about 1 mole of a bis-activated substantially non-antigenic polymer under conditions sufficient to effect covalent conjugation of the interferon and polymer. Methods of treating interferon-susceptible conditions with the compositions of the present invention are also disclosed.

Interferon polymer conjugates and process for preparing the same

A process is disclosed for preparing long-acting alpha interferon-containing compositions. Alpha interferon is contacted with a relatively small molar excess of a substantially non-antigenic polymer in the presence of a surfactant to preserve bioactivity. Isolation of the desired conjugate species having optimal activity is also disclosed.

Conjugates containing glucocerebrosidase and non-antigenic polymers such as polyethylene glycol are disclosed. The conjugates circulate for extended times and have prolonged activity in vivo when compared to unmodified enzymes. The conjugates are useful in the treatment of Gaucher's Disease and have improved enzyme activity at the pH ranges associated with lysosomal, arterial and capillary regions.

Glycolipid enzyme-polymer conjugates

Polyalkylene oxide-conjugated hemoglobin solutions having a molecular weight greater than about 85,000 daltons and a degree of substitution of which substantially avoids clinically significant nephrotoxicity associated with hemoglobinuria in mammals. A method of simultaneously fractionating and purifying polyalkylene oxide-conjugated hemoglobins is al so disclosed.

Growing community of inventors

Basking Ridge, NJ, United States of America

Carl W Gilbert