Albert Einstein College of Medicine

La Jolla Bioengineering Institute

Belur N Manjula

Seetharama A Acharya

Paul K Smith

A Seetharama Acharya

Parimala Nacharaju

Pedro Cabrales

Amy Tsai

The present invention provides PEGylated hemoglobins and PEGylated albumins comprising polyethylene glycol (PEG) conjugated to hemoglobin or to albumin, wherein the PEG is a maleimide PEG, an alkylamide PEG, an iodoacetamide PEG, a p-nitro thio-phenyl PEG, a vinyl sulfone PEG, or a mixed disulfide PEG; and PEGylated albumins and PEGylated hemoglobins comprising polyethylene glycol (PEG) attached to a thiolated amino group of albumin or hemoglobin, wherein the amino group is thiolated using dithio sulfo succinimidyl propionate (DTSSP) or dithiosuccinimidyl propionate (DTSP) or dithiobispropionimidate. The invention also provides methods of preparing PEGylated hemoglobins and PEGylated albumins comprising a) reacting hemoglobin or albumin with a thiolating agent and with a PEGylating agent, and b) capping unPEGylated reactive thiols of hemoglobin or albumin with N-ethyl maleimide.

Pegylated albumin and uses thereof

Provided are hemoglobins having at least two chemical modifications that lower oxygen affinity, hemoglobins chemically modified by the addition of glyceraldehyde-3-phosphate, and hemoglobins having at least two specific chemical modifications. PEGylated versions of these hemoglobins are also provided, as are certain tetraPEGylated and diPEGylated hemoglobins. Methods of modifying a hemoglobin are additionally provided, as are methods of making a hemoglobin. Pharmaceutical compositions and blood substitutes using these hemoglobins are further provided, as are methods of treating a subject using these pharmaceutical compositions and blood substitutes.

Second generation low oxygen affinity pegylated hemoglobins as oxygen-carrying plasma expanders

The present invention is directed to uses of PEGylated albumins which include methods of treating reduced functional capillary density, reduced blood volume, septic shock and cardiac arrhythmia in a subject, which comprise administering to the subject a therapeutically effective amount of a PEGylated albumin.

Uses of pegylated albumin

The present invention is directed to pegylated red blood cells comprising a polyethylene glycol (PEG) attached to a thiolated amino group on a membrane protein, and to compositions comprising the pegylated red blood cells. The invention also provides methods of preparing pegylated red blood cells comprising reacting red blood cells with a compound that produces a thiolated amino group on a red blood cell membrane protein, and reacting the thiolated red blood cell with a PEG. The invention further provides methods of treatment using pegylated red blood cells.

Universal red blood cells, methods of preparing same, and uses thereof

The present invention provides a hemoglobin molecule (Hb) having six &#xb1; one PEG chains, wherein two of said PEG chains are bound to Cys-93 (&#x3b2;) of Hb, and the remaining PEG chains are bound to thiol groups introduced on &#x3b5;-NHof Hb. The present invention also provides a process for preparing a modified hemoglobin molecule (Hb), comprising the steps of: (a) reacting Hb with 8-15 fold excess of iminothiolane to form thiolated Hb; and (b) reacting the thiolated Hb with 16-30 fold excess of PEG functionalized with a maleimide moiety, to form the modified Hb.

Modified hemoglobin and methods of making same

Novel modified hemoglobins comprising polyalkylene glycols and novel methods for making those hemoglobins are provided. One group of modified hemoglobins comprise polyalkylene glycols bonded to the hemoglobin with an amide linkage at Glu-43(&#x3b2;). Additional polyalkylene glycols can also be bonded to the Glu-22(&#x3b2;) and/or the Asp-47(&#x3b2;). These hemoglobins are made by a novel amidation procedure. A second group of modified hemoglobins comprise a polyalkylene glycol covalently bonded to the hemoglobin at the &#x3b1;-amino of a Val-1(&#x3b2;) or a Val-1(&#x3b1;). Additional polyalkylene glycols can optionally be covalently bonded to a limited number of &#x3b5;-amino groups. This second group of hemoglobins is made using a novel reductive alkylation procedure. A third group of modified hemoglobins comprise a polyalkylene glycol bonded to a thiol group of the hemoglobin through a phenylsuccinimido linkage, wherein no polyalkylene glycol is bonded to a Cys-93(&#x3b2;). This third group of modified hemoglobins is made by an improvement in a hemoglobin-polyalkylene linkage procedure utilizing thiolation-mediated maleimide chemistry.

Size enhanced hemoglobins: surface decoration and crosslinking of the protein with polyoxy alkylene glycols

The present invention provides pegylated hemoglobins comprising a thiocarbamoyl-phenyl-polyethylene glycol (PEG) attached to hemoglobin, and comprising a polyethylene glycol (PEG) attached to hemoglobin by an acyl group. The invention also provides methods of preparing pegylated hemoglobins using isothiocyanato phenyl carbamate of PEG and using isothiocyanato phenyl di-PEG carbamate. The invention further provides compositions and blood substitutes comprising pegylated hemoglobins and methods of treating a subject which comprise administering to the subject blood substitutes comprising non-hypertensive pegylated hemoglobins.

Pegylated non-hypertensive hemoglobins, methods of preparing same, and uses thereof

The present invention provides a class of compounds having the formula:

Growing community of inventors

Cresskill, NJ, United States of America

Belur N Manjula