Cluster clearing agents

• US 6,908,903 B1
• Filed: 10/12/2000
• Issued: 06/21/2005
• Est. Priority Date: 12/07/1994
• Status: Expired due to Fees

• Current Assignee: Aletheon Pharmaceuticals, Inc.
• Original Assignee: Aletheon Pharmaceuticals, Inc.
• Inventors: Axworthy, Donald B., Theodore, Louis J.
• Primary Examiner(s): Canella, Karen A.
• Application Number:
  US09/687,055
• Time in Patent Office: 1,713 Days
• Field of Search: 514/23, 514/24, 514/54, 514/62, 424/178.1
• US Class Current: 514/24
• CPC Class Codes: A61K 47/557 the modifying agent being biotin
• CPC Class Codes: A61K 47/6893 clearing therapy or enhanced clearance, i.e. using an antibody clearing agents in addition to T-A and D-M
• CPC Class Codes: A61K 47/6898 using avidin- or biotin-conjugated antibodies
• CPC Class Codes: A61K 51/1268 host-guest, closed hollow molecules, inclusion complexes, e.g. with cyclodextrins, clathrates, cavitates, fullerenes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Cluster clearing agents (CCAs) and the use thereof are discussed. CCAs are composed of a hepatic clearance directing moiety which directs the biodistribution of a CCA-containing construct to hepatic clearance; and a binding moiety which mediates binding of the CCA to a compound for which rapid hepatic clearance is desired.

Claims

1. A method of delivering an active agent to a targeted in vivo site comprising:

(a) administering to a recipient a first conjugate comprising a targeting moiety and a member of a ligand/anti-ligand binding pair;

(b) thereafter administering to the recipient a clearing agent capable of directing the clearance of circulating first conjugate; and

(c) subsequently administering to the recipient a second conjugate comprising an active agent and a ligand/anti-ligand binding pair member, wherein the second conjugate binding pair member is complementary to that of the first conjugate;

wherein the clearing agent comprises;

(i) a hepatic clearance directing moiety comprising an iterative, two branch chemical framework to which a plurality of hexose residues are bound, wherein the plurality of hexose residues are a plurality of 1-desoxy-1-thio-N-acetylgalactosamine hexose residues; and

(ii) a binding moiety directly or indirectly attached to the hepatic clearance directing moiety, wherein the binding moiety binds in vivo a compound to be cleared,

wherein the clearing agent is characterized by a molecular mass between about 2,000 and about 20,000 daltons, and directs clearance of the compound by a hepatic pathway.

2. A method of delivering an active agent to a targeted in vivo site comprising:

(a) administering to a recipient a first conjugate comprising a targeting moiety and a member of a ligand/anti-ligand binding pair;

(b) thereafter administering to the recipient a clearing agent capable of directing the clearance of circulating first conjugate; and

(c) subsequently administering to the recipient a second conjugate comprising an active agent and a ligand/anti-ligand binding pair member, wherein the second conjugate binding pair member is complementary to that of the first conjugate;

wherein the clearing agent comprises;

(i) a hepatic clearance directing moiety comprising an iterative, two branch chemical framework to which a plurality of hexose residues are bound, wherein the plurality of hexose residues are a plurality of N-acetyl-galactosamine residues; and

(ii) a binding moiety directly or indirectly attached to the hepatic clearance directing moiety, wherein the binding moiety binds in vivo a compound to be cleared,

wherein the clearing agent is characterized by a molecular mass between about 2,000 and about 20,000 daltons, and directs clearance of the compound by a hepatic pathway, and

wherein the clearing agent is selected from the following;

wherein n ranges from about 4 to about 8;

m and o range from about 3 to about 6;

p ranges from about 1 to about 10;

R′

is H or lower alkyl of from 1 to about 6 carbon atoms; and

R is lower alkyl from about 1 to about 6 carbon atoms, phenyl, benzyl or C_2-6 lower alkyl substituted with phenyl.

3. The method of claim 2 wherein the clearing agent of claim 2 is selected from the third chemical formula of claim 2, wherein n is 5, m is 5, o is 5, p is 1, R′

is H, and R is methyl.

4. The method of claim 2 wherein in the clearing agent of claim 2 p is 2 or 3;

and R are a straight chain lower alkyl of 2 carbon atoms.

5. The method of claim 4 wherein in the clearing agent of claim 4 n is 5;

m is 5;

o is 5; and

R′

is H.

6. The method of claim 2 wherein in the clearing agent of claim 2 p is 2 or 3;

and R are a straight chain lower alkyl of 1 carbon atom.

7. The method of claim 2 wherein in the clearing agent of claim 2 p is 2 or 3;

and R are a straight chain lower alkyl of 1 carbon atom and a straight chain lower alkyl of 2 carbon atoms.

8. The method of claim 7 wherein in the clearing agent of claim 7 n is 5;

m is 5;

o is 5; and

R′

is H.