Adprotech Limited

Richard Anthony Godwin Smith

Danuta Ewa Irena Mossakowska

Ian Dodd

Vivienne Frances Cox

Steven Howard Sacks

Colin Michael Edge

Julian Roy Pratt

Danuta Ewa Irena Mossakowkska

Pamela Jane Elizabeth Rowling

This invention relates to formulations of polypeptides and their derivatives that act as inhibitors or regulators of the immune or coagulation systems and are of use in organ transplantation. It provides solutions which include, for example, complement inhibitors or regulators of T- or B-lymphocyte function in modified molecular forms that can be used to perfuse and modify organs prior to transplantation or to store organs prior to transplantation, and to localise agents on organs. It further provides for a preparation for perfusion of an organ prior to transplantation or storage of the organ comprising: a soluble derivative of a soluble polypeptide, said derivative comprising two or more heterologous membrane binding elements with low membrane affinity covalently associated with the polypeptide which elements are capable of interacting, independently and with thermodynamic additivity, with components of membranes of the organ exposed to extracellular perfusion fluids; and a physiologically acceptable flush storage solution.

Method of preparing an organ by perfusion

The present invention provides, among other things, soluble derivatives of soluble polypeptides that incorporate membrane binding elements. Methods of making these soluble derivatives, and methods of using these soluble derivatives also are provided.

Conjugates of soluble peptidic compounds with membrane-binding agents

Replacement of codons in DNA encoding the first three SCRs of LHR-A of CR1 with others encoding the predicted amino acids in the CR1-like sequence can give rise to chimeric genes which can be expressed to give active complement inhibitors with functional complement inhibitory, including anti-haemolytic activity. There is provided a soluble polypeptide comprising, in sequence, one to four short consensus repeats (SCR) selected from SCR 1, 2, 3 and 4 of long homologous repeat A (LHR-A) as the only structurally and functionally intact SCR domains of CR1 and including at least SCR3, in which one or more of the native amino acids are substituted with the following: Val 4, Asp 19, Scr 53, Lys 57, Ala 74, Asp 79, Arg 84, Pro 91, Asn 109, Lys 116, Val 119, Ala 132, Thr 137, Ile 139, Ser 140, Tyr 143, His 153, Leu 156, Arg 159, Lys 161, Lys 177, Gly 230, Ser 235, His 236.

Complement receptor type 1 (CR1)-like sequences

A polypeptide comprising a portion of the sequence of the general formula (I): CNPGSGGRKVFELVGEPSIYCTSNDDQVGIWSG, of 6-23 amino acids in length and comprising sequence a) and/or b): a) GGRKVF, b) FELVGEPSIY multimeric and chimeric derivatives, pharmaceutiocal compositions containing them and their use in therapy.

Fragments of CR1 and their use

The invention provides a linear concatamer of at least two non-identical DNA sequences which, by virtue of third base redundancy of the genetic code of the codons, each encode the same polypeptide of at least 30 amino acids; wherein the concatamer comprises or consists of a nucleic acid sequence which codes for an oligomer of said polypeptides in a continuous reading frame. A single invariant cysteine codon may be added to one DNA sequence to encode a polypeptide derivative with a unique unpaired cysteine. The concatamer may be fused to one or more sequences encoding one or more antigens. The DNA sequences in the concatamer may encode the compliment C3 fragment C3d or an analogue thereof. The invention also provides an expression vector comprising the concatamer nucleic acid sequence and regulatory or other sequences for expression of any oligomeric polypeptide encoded thereby, as well as a host cell comprising the expression vector. The invention can also provide a method of including a immune response to an antigen in the human or animal by administering a concatamer or administering a vector. Thus the invention can provide a pharmaceutical composition in the form of a DNA vaccine.

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Herts, United Kingdom

Richard Anthony Godwin Smith