Title:  Transcytosis vehicles and enhancers for drug delivery

United States Patent:  6,204,054

Assignee:  Andaris Limited (GB)

Filed:  June 25, 1998

PCT NO:  PCT/GB96/02326

102(e) Date:  June 25, 1998

PCT PUB. Date:  March 27, 1997

Foreign Application Priority Data:  Mar 26, 1996[GB] (9606315)

Transcytosis of a physiologically-active agent that exerts its action following passage across endothelia, epithelia or mesothelia containing the GP60 receptor is enhanced by formulation with or conjugation to a transcytosis enhancer or vehicle selected from albumin and fragments thereof, anti-GP60 antibody and fragments thereof, GP60 peptide fragments, and PDI (protein disulphide isomerase) and fragments thereof.

SUMMARY OF THE INVENTION

The present invention provides transcytosis vehicles and enhancers capable of transporting physiologically-active agents across epithelia, endothelia and mesothelia containing the GP60 receptor. The GP60 receptor has been implicated in receptor-mediated transcytosis of albumin across cell barriers. By means of the invention, GP60 receptor-mediated transcytosis can be exploited for the transport of not only albumin, but also physiologically-active agents which do not naturally pass through epithelia, endothelia and mesothelia via the GP60 system.

Transcytosis vehicles and enhancers of the invention include albumin, albumin fragments, anti-GP60 polyclonal and monoclonal antibodies, anti-GP60 polyclonal and monoclonal antibody fragments, and GP60 peptide fragments. Further, they include PDI (protein disulphide isomerase) and fragments thereof (any subsequent reference to GP60 fragments may be interpreted as referring also to PDI fragments). A common factor may be a CGMC motif found in PDI and at least the T_1-44 fragment of GP60. If the transcytosis vehicle or enhancer is a GP60 peptide fragment, it is preferably co-administered with other transcytosis vehicles or enhancers of the present invention such as albumin or an albumin fragment. Suitable albumin fragments of 14, 20 and 32 kDa can be generated by cleavage at methionine residues using cyanogen bromide and can be further reduced in size by reduction of disulfide bridges. Anti-GP60 polyclonal and monoclonal antibody fragments useful as transcytosis vehicles and enhancers according to the present invention include Fab, Fab', F(ab')₂, and Fv fragments. Preferred GP60 peptide fragments include the T3118 peptide which corresponds to the N-terminal 18 amino acids of the GP60 protein.

In accordance with the invention, when the above compounds are conjugated to a physiologically-active agent, they are referred to herein as "transcytosis vehicles". When co-administered with but not conjugated to a physiologically-active agent, the above compounds are referred to herein as "transcytosis enhancers". In preferred embodiments, the transcytosis vehicles and enhancers of the present invention are useful for delivering or enhancing passage of physiologically-active agents across endothelia of the vasculature, alveolar epithelia and peritoneal mesothelia.

Claim 1 of 15 Claims

What is claimed is:

1. A composition comprising, or conjugate of, a physiologically-active agent that exerts its action following passage across endothelia, epithelia or mesothelia containing the GP60 receptor, and a transcytosis enhancer or vehicle selected from albumin and fragments thereof, anti-GP60 antibody and fragments thereof, GP60 peptide fragments, and PDI (protein disulphide isomerase) and fragments thereof; wherein said composition or conjugate is a dry powder suitable for inhalation.

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