Vasopermeability enhancing peptide of human interleukin-2 and immunoconjugates thereof
AssigneeUniversity of Southern California
InventorsAlan L. Epstein, Leslie A. Khawli
Life of this patent
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Abstract
A novel permeability enhancing peptide (PEP) is a fragment of interleukin-2. When joined to a delivery vehicle that can target a tumor site, the PEP can increase the subsequent uptake of antineoplastic or tumor imaging agents. The PEP can be chemically joined to a monoclonal antibody to form an immunoconjugate. Alternatively, an expression vector is genetically engineered to express a fusion protein. The fusion protein has an antigen-binding portion joined to the PEP. The PEP is most effective when it takes the form of a dimer, linked by a disulfide bridge. The PEP is substantially free of cytokine activity and produces minimal toxic side effects on normal tissues.
Claims27
A vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier.
A conjugate comprising:
- a) a delivery vehicle having the ability to localize at the site of neoplastic tissue;
- and
- b) a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle.
A fusion protein comprising:
- a) a delivery vehicle having the ability to localize at the site of neoplastic tissue, the vehicle having at least one terminal amino acid;
- and
- b) at least one vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, the peptide being joined to at least one terminal amino acid of the delivery vehicle by genetic engineering.
A vector for the expression of fusion protein, comprising:
- a) a fusion protein sequence comprising;
- 1) a delivery vehicle encoding sequence, said delivery vehicle having the ability to localize at the site of neoplastic tissue, and
- 2) a vasoactive peptide encoding sequence, said vasoactive peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide encoding sequence having substantial homology to SEQ ID NO. 2 and having a reading frame that permits co-expression of at least one segment of said delivery vehicle encoding sequence;
- and
- b) an expression vector having an insertion site for the fusion protein sequence and being capable of expressing the fusion protein in cells.
A method for the therapy of neoplastic tissue, comprising:
- a) administering to a host having said tissue an effective amount of a conjugate, said conjugate comprising:
- a delivery vehicle having the ability to localize at the site of neoplastic tissue;
- and
- a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- b) contemporaneously or thereafter administering to said host an antineoplastic therapeutic agent.
A method for the therapy of neoplastic tissue, comprising, administering to a host having said tissue an effective amount of a conjugate, said conjugate comprising:
- a) a delivery vehicle having the ability to localize at the site of neoplastic tissue;
- b) a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- c) a tumoricidal agent.
A method for the diagnosis of neoplastic tissue, comprising:
- a) administering to a host having said tissue an effective amount of a conjugate, said conjugate comprising:
- a delivery vehicle having the ability to localize at the site of neoplastic tissue, and
- a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- b) contemporaneously or thereafter administering to said host a tumor imaging agent.
A method for the diagnosis of neoplastic tissue, comprising, administering to a host having said tissue an effective amount of a conjugate, said conjugate comprising:
- a) a delivery vehicle having the ability to localize at the site of neoplastic tissue,
- b) a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- c) a detectable label.
A therapeutic kit, comprising:
- a) a conjugate, said conjugate comprising:
- a delivery vehicle having the ability to localize at the site of neoplastic tissue, and
- 2) a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- b) an antineoplastic therapeutic agent.
A diagnostic kit, comprising:
- a) a conjugate, said conjugate comprising:
- 1) a delivery vehicle having the ability to localize at the site of neoplastic tissue, and
- 2) a vasoactive peptide, said peptide comprising a fragment of interleukin-2, substantially free of cytokine activity, said vasoactive peptide being capable of enhancing vascular permeability when joined to a carrier, said peptide being connected to said delivery vehicle;
- and
- b) a tumor imaging agent.
Dependencies are inferred from the claim text.