Molecular conjugates containing cell membrane-blending agents

• US 5,149,782 A
• Filed: 08/19/1988
• Issued: 09/22/1992
• Est. Priority Date: 08/19/1988
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Tanox Biosystems Inc. (Roche Holding AG)
• Inventors: Gordon, Wayne, deVilliers, Jean, Chang, Tse-wen
• Primary Examiner(s): Nucker, Christine M.
• Assistant Examiner(s): KIM, KAY KWANG AE
• Application Number:
  US07/234,399
• Time in Patent Office: 1,495 Days
• Field of Search: 530/390, 530/391, 530/408, 530/409, 530/326, 530/324, 530/322, 530/345, 530/377, 530/410, 530/391.1, 530/391.7, 530/391.9, 536/27, 536/28, 536/29
• US Class Current: 530/326
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers

Abstract

Molecular conjugates which facilitate the attachment of macromolecular drugs onto cellular surfaces and their entry into cells are described. The molecular conjugates comprise a macromolecular drug linked to an "inactivated" membrane blending agent which inserts into the cellular plasma membrane. The membrane blending agent is inactivated by cleavable linkage to a blocking agent which, until released from the conjugate under appropriate conditions, blocks and ability of the membrane blending agent to insert into the cellular membrane. Upon release of the blocking agent, the membrane blending agent is "activated" and the conjugate can be inserted into a cellular plasma membrane. The membrane blending agents can be peptides such as fusogenic or ion channel forming peptides or long chain fatty acids. The blocking agents can be bulky or charged moieties which mask and prevent insertion of the membrane blending agent.

Claims

1. A molecular conjugate, comprising a macromolecular drug linked to a substantially hydrophobic membrane blending agent which can blend with an insert into a cellular membrane, the agent being cleavably linked to a blocking agent which blocks the ability of the membrane blending agent to insert into a cellular membrane.

2. A molecular conjugate of claim 1, wherein the drug is a polypeptide, protein, glycoprotein or nucleic acid.

3. A molecular conjugate of claim 1, wherein the membrane blending agent which can insert into a cellular membrane is a fusogenic peptide or a portion thereof.

4. A molecular conjugate of claim 3, wherein the fusogenic peptide has the amino acid sequence:

space="preserve" listing-type="equation">RERRAVGIGALFLGFLGAAGK.

5. A molecular conjugate of claim 1, wherein the blocking agent is also a targeting agent.

6. A molecular conjugate of claim 5, wherein the targeting agent is an antibody specific for a cellular surface antigen.

7. A molecular conjugate of claim 1, wherein the cleavable linkage between the membrane blending agent and the blocking agent is a disulfide linkage.

10. The molecular conjugate of claim 1 wherein the membrane blending agent is a fatty acid.

11. The molecular conjugate of claim 10 wherein the fatty acid is palmitic acid.

8. A molecular conjugate comprising a fusogenic peptide having the amino acid sequence RERRAVGIGALFLGFLGAAGK cleavably linked to a blocking agent which blocks the ability of the fusogenic peptide to insert into a cellular membrane.

9. A molecular conjugate comprising two inter-linked substantially hydrophobic membrane blending agents which can blend with and insert into a cellular membrane, in which the membrane blending agents are cleavably linked to blocking agents that block the ability of the interlinked membrane blending agent to insert into the cellular membrane.