The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

The present invention is related to a compound comprising a cyclic peptide of formula (I)

##STR00001## and an N-terminal modification group A attached to Xaa1, wherein each and any one of Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6 and Xaa7 is a residue of an amino acid, and Yc is a structure of formula (X)

##STR00002##

The invention relates to improvements in drug delivery and more particularly to the use of Cell Penetrating Agents (CPA's) or Cell Penetrating Peptides (CPP's) which have been stabilized by, for example: i) stapling two amino acids to form Stapled CPP's (StaP's) or ii) stitching three or more amino acids to form stitched CPP's (StiP's). These stabilized CPP's are conjugated to a drug or Biologically Active Compound (BAC) directly or via a Bi-Functional Linker (BFL) so that the BAC can be carried through a cell membrane by the CPP. The resulting molecules are referred to as Drug Carrying Cell Penetrating Molecules (DCCPM's). The preferred BAC is an electrically low charge carrying oligonucleotide such as a phosphorodiamidate morpholino oligonucleotide (PMO). The invention also relates to a method of facilitating the uptake of a BAC into a cell, the use of a DCCPM in the treatment of a disease requiring alteration of an endogenous or exogenous gene, a method of improving the bioavailability of a drug or BAC, a method of introducing a drug or BAC to a site which is refractory to the drug or BAC in its native state, a method of treating a subject comprising administering the DCCPM's of the invention and to a pharmaceutical composition comprising the DCCPM and one or more pharmaceutically acceptable excipients.

The invention relates to improvements in drug delivery and more particularly to the use of Cell Penetrating Agents (CPA's) or Cell Penetrating Peptides (CPP's) which have been stabilized by, for example: i) stapling two amino acids to form Stapled CPP's (StaP's) or ii) stitching three or more amino acids to form stitched CPP's (StiP's). These stabilized CPP's are conjugated to a drug or Biologically Active Compound (BAC) directly or via a Bi-Functional Linker (BFL) so that the BAC can be carried through a cell membrane by the CPP. The resulting molecules are referred to as Drug Carrying Cell Penetrating Molecules (DCCPM's). The preferred BAC is an electrically low charge carrying oligonucleotide such as a phosphorodiamidate morpholino oligonucleotide (PMO). The invention also relates to a method of facilitating the uptake of a BAC into a cell, the use of a DCCPM in the treatment of a disease requiring alteration of an endogenous or exogenous gene, a method of improving the bioavailability of a drug or BAC, a method of introducing a drug or BAC to a site which is refractory to the drug or BAC in its native state, a method of treating a subject comprising administering the DCCPM's of the invention and to a pharmaceutical composition comprising the DCCPM and one or more pharmaceutically acceptable excipients.

This invention discloses certain methods of treating acute pancreatitis and inflammatory pancreatic disease or condition. The disclosed peptides and analogs can significantly lower the elevated blood amylase and lipase levels caused by acute pancreatitis and pancreatic inflammation, reduce the degree of injury observed in pancreatic histopathology caused by pancreatitis, and significantly lower the mortality rate of acute pancreatitis.

The present disclosure relates to a linker molecule for targeting molecule-drug conjugate, and the corresponding conjugate, the preparation and use thereof.

Disclosed are ophthalmic compositions, methods for using the compositions and kits comprising the compositions for treating dry eye in a subject in need thereof. The composition comprises at least one peptide that is an inhibitor of trans-endothelial migration, an analogue, variant, derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for treating dry eye and ocular diseases of inflammation.

Disclosed are ophthalmic compositions, methods for using the compositions and kits comprising the compositions for treating dry eye in a subject in need thereof. The composition comprises at least one peptide that is an inhibitor of trans-endothelial migration, an analogue, variant, derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for treating dry eye and ocular diseases of inflammation.

A bio-related substance bonded to a branched and degradable polyethylene glycol derivative that is degraded in the cells represented by the following formula (A):

##STR00001##

wherein each symbol is as defined in the present specification, is provided by the present invention.

A multi-arm, degradable polyethylene glycol derivative with a high molecular weight that does not cause vacuolation of cells is provided. A degradable polyethylene glycol derivative represented by the following formula (1):

##STR00001##

wherein n1 and n2 are each independently 45-950, W.sup.1 and W.sup.2 are each independently an oligopeptide of 2-47 residues, a1 and a2 are each independently 1-8, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom and/or a nitrogen atom, X.sup.1 and X.sup.2 are each independently a functional group capable of reacting with a bio-related substance, and L.sup.1, L.sup.2, L.sup.3, L.sup.4, L.sup.5 and L.sup.6 are each independently a divalent spacer.