Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1993-01-15
1995-08-15
Lacey, David L.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
4242341, 4242361, 530350, 530380, 514 6, 514 8, A61K 3128, A61K 3130, A61K 31315, C07K10300
Patent
active
054417376
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention relates to the use of apotransferrin that has bound divalent zinc or copper ions as an agent for prophylactic and therapeutic treatment of the toxic effects of endotoxins. Apotransferrin is a glycoprotein with an average molecular weight of 80,000 Dalton. It can bind mainly trivalent iron ions reversibly. It can also bind other metal ions instead of iron such as Cu(II), Mn(III), Co(III) or Zn(II). In human and animal organisms, apotransferrin usually occurs as transferrin, a protein-metal complex with trivalent iron.
The main function of apotransferrin is considered to be its ability to bind and transport specific trivalent iron ions, whereby it can bind and transport one or two molecules of iron reversibly. In this way, the iron is transported following its absorption in the small intestine to the iron depots in the liver and spleen as well as in the reticulocytes in the hematopoietic tissue. The normal range of plasma apotransferrin-iron complex (transferrin) concentration is 200 mg/dl to 400 mg/dl.
A further important function of transferrin in its iron-free form is considered to be its bacteriostatic effect (Martin CM, Jandl JH, Finland M. J Infect Dis 1963; 112:158-163; Fletcher J. Immunology 1971; 20:493-500). Iron is an essential growth factor for bacteria. The complexing of iron by transferrin keeps the free iron concentration in the plasma under the minimum required for bacterial growth. Berger und Beger (Berger D, Beger HG. Clin Chim Acta 1987; 163:289-299; Arzneim-Forsch/Drug Res 1988; 38:817-820; and Prog Clin Biol Res 1988; 272:115-124) concluded on the basis of the bacteriostatic effect of transferrin that transferrin in its iron-free form might even fulfil the function of an adjunctive anti-microbial agent in extensive gram-negative infections in the sense of a complement to conventional antibiotic therapy.
Apotransferrin that has bound trivalent iron, i.e. in its form as transferrin, is also capable of reducing the biological activity of endotoxins. The ability of transferrin to neutralize endotoxin increases along with the iron load as is described in detail in DE 38 42 143 and DE 38 44 667. The fact that apotransferrin, having bound iron ions, is more or less capable of neutralizing endotoxins, depending on the iron level, does not necessarily mean that the same effect will achieved when other metal ions are bound.
In contrast to the conclusions described in DE 38 42 143 and in DE 3844 667, Berger et al. report that ". . . the endotoxin binding capacity is restricted to apotransferrin." (Berger D, Winter M, Beger HG. Clin Chim Acta 1990; 189:1 (Summary)) and that the ability of apotransferrin to bind and neutralize endotoxin is reduced when iron is bound (Berger D, Beger HG. Clin Chim Acta 1987; 163:289-299; Arzneim-Forsch/Drug Res 1988; 38:817-820; and Prog Clin Biol Res 1988; 272: 115-124; Langenbecks Archiv fur Chirurgie 1990; Suppl. 1-6; Berger D, Winter M, Beger HG. Clin Chim Acta 1990, 189: p. 1-6). The authors even mention that "transferrin . . . exhibits endotoxicity enhancing activity." (Berger D, Winter M, Beger HG. Clin Chim Acta 1990; 189: p. 4). Berger et al. also report that, besides pH, the presence of divalent cations (Ca.sup.2+, Mg.sup.2+, Mn.sup.2+) in the reaction medium is of decisive importance regarding the binding of endotoxin by apotransferrin (Berger D, Beger HG. Arzneim-Forsch/Drug Res 1988; 38:817-820; Prog Clin Biol Res 1988; 272: 115-124; Berger D, Winter M, Beger HG. Clin Chim Acta 1990, 189: p. 1-6 and Berger D, Kitterer WR, Beger HG. Eur J Clin Invest 1990; 20:66-71). The authors merely mention that divalent cations must be present in the reaction mixture at a concentration of 2 mmol/l or 3 mmol/l (Mg.sup.2+) and do not describe a potential influence of ion concentration on the binding of endotoxin. The authors do not conclude that an increase in the ion concentration in the solution, and an indirectly related increase in apotransferrin-cation complexes, result in an improvement of endotoxin binding by apotransferr
REFERENCES:
patent: 5045466 (1991-09-01), Morrison et al.
Osband, M. E. et al., Immunology Today, 11(6):193-195, 1990.
Cross, A. S., et al., Infection and Immunity, 61(7):2741-2747, Jul. 1993.
Biological Abstracts, M. C. McGahan, "Copper and Aspirin Treatment Increase the Antioxidant Activity of Plasma", vol. 90, (1990), Ref. No. 126999.
Lacey David L.
Larson Herbert W.
Loring Susan A.
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