Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-02-06
1998-08-11
Feisee, Lila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 530300, 530412, A61K 3800, C07K 1400
Patent
active
057927448
DESCRIPTION:
BRIEF SUMMARY
The present invention refers to proteins from animal tissues, particularly from mammalian liver, and to the use thereof in oncology.
WO 92/10197 discloses extracts of mammalian organs, particularly of goat liver, consisting of at least three different proteins and characterized by unusual pharmacological and immunological properties. No information was reported on the actual role and on the sequences of the individual protein components.
A 23-KDa dimeric protein extracted with 5% perchloric acid from rat liver and kidney has been disclosed in Eur. J. Biochem. 212, 665, 1993. The corresponding cDNA sequence have been deposited at the EMBL data bank under accession number X70825.
This protein, reported to be co-extracted with High-mobility group (HMG) proteins, is suggested to play a role in the folding of proteins, so that it could be considered as one member of the class of the so-called "chaperons" or chaperonins.
WO 93/18146 discloses a protein extracted from rabbit-liver having a molecular weight of 59 Kd capable of complexing with chaperons and a heat shock protein of 90 Kd.
A new protein purified from the extract disclosed in WO 92/10197, has been found now having the partial aminoacid sequence depicted in sequence Id No. 1.
Said protein is useful in oncology in view of the following properties: against human tumor cell cultures; .mu.g/kg in Balb/c mice having a murine colon adenocarcinoma (c26) and in rats with intrapleuric Yoshida ascitic tumor; recognize human carcinoma cells.
Said properties explain the activity observed in clinical tests carried out administering the extract of WO 92/10197 to patients affected by advanced cancer of the lung, breast, stomach, colon and liver.
The protein of the invention has a high degree of homology with that extracted from rat liver disclosed in Eur. J. Biochem. 212, 665, 1993.
Proteins having a high degree of homology with that of Sequence Id No. 1 have also been found in liver of different animal species, particularly bovine and equine liver.
A new protein family has been therefore found: the members of this previously unknown family are characterized by an high degree of conservation and homology between the mammalian species and a molecular weight ranging from about 10 KDa to about 14 KDa.
The term "high degree of homology" means an homology of the aminoacid sequences of about 80% or higher, preferably of 90% or higher.
The invention further refers to the use in oncology, as a therapeutic and/or diagnostic tool, of the above mentioned perchloric acid extractable proteins from mammalian liver.
The invention provides therefore pharmaceutical compositions containing the protein having the partial amino acid sequence No. 1 or proteins having at least 80% homology, preferably at least 90% homology, with Sequence Id No. 1.
The pharmaceutical compositions of the invention will be administered by parenteral route, preferably subcutaneously or intra-muscularly and will typically contain from 0.1 to 50 mg of total protein per unit dose. The protein active principle, purified by conventional methods, may be lyophilized on a suitable non-toxic carrier and distributed in vials or bottles.
Suitable solvents include sterile water or saline solutions.
According to a further embodiment of the invention, the proteins of the invention or fragments thereof, produced for instance by chemical synthesis, may be used to produce polyclonal or monoclonal antibodies. Particularly interesting antibodies recognize tumoral antigens and are therefore useful for diagnostic, therapeutic or research purposes. Two of said antibodies have been deposited on 27 Jul., 1993 at the European collection of Animal Cell Cultures (EGACC), Porton Down, Salisbury, UK under accession numbers 930806103 and 930806104.
These antibodies were used in immunocytochemical tests on several bioptic samples of human cancers, enabling their recognition.
The proteins of the invention, when administered to patients affected by neoplastic disease, in addition to advantageous effects such as inhibition or regression of th
REFERENCES:
Reeck et al (Cell, 1987, 50:667).
Lewin (Science, 1988, 237:1570).
Eur. J. Biochem, (1993), 212(3), 665-73, "Characterization, purification and cDNA cloning of a rat perchloric-acid-soluble 23-kDa protein present only in liver and kidney", Levy-Favatier et al.
Database EMBL, Emrod:Respspl; Access-no: D49363, "Sequence of PSP1", T. Oka, 22, Feb. 1995, See Abstract.
Database EMBL, Emest:Hs68065, Access-no: T98680, "The WashU-merck EST Project", L. Hillier et al, 17 Apr. 1995, See Abstract.
Bartorelli Alberto
Ronchi Severino
Feisee Lila
Ungar Susan
Zetesis S.p.A.
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