Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1996-06-06
2001-01-09
Duffy, Patricia A. (Department: 1645)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C514S025000
Reexamination Certificate
active
06172045
ABSTRACT:
TECHNICAL FIELD
The present invention relates to cluster clearing agents (CCAs), reagents for the preparation thereof and associated methods and compositions. CCAs impact the elimination and biodistribution of constructs that incorporate or become associated with such agents in a manner resulting in increased elimination via a hepatic route. The CCA-associated constructs also generally exhibit a decreased serum half-life in comparison to counterpart compounds which do not incorporate or become associated with CCAs.
BACKGROUND OF THE INVENTION
Conventional cancer therapy is limited by the problem that the generally attainable targeting ratio (ratio of administered dose of active agent localizing to tumor versus administered dose circulating in blood) is low. This limitation is generally encountered in systemic administration of chemotherapeutic agents as well as in administration of monoclonal antibody-active agent conjugates. Systemic administration involves exposure of healthy tissue to the active agent. Also, as a result of the relatively long half life of a monoclonal antibody, non-target tissue is exposed to circulating antibody-active agent conjugate. Improvement in targeting ratio is therefore sought.
A method employed to improve targeting ratio is referred to generally as pretargeting. In pretargeting, a targeting moiety is formed of a targeting agent and a receptor. The active agent is associated with a ligand for the receptor. The targeting moiety is administered to a recipient, and permitted to localize to the target site with binding at that site mediated by the targeting agent. When target site localization and sufficient elimination of circulating targeting moiety is achieved by the recipient's metabolism, the active agent-ligand is administered. The ligand component of the construct binds to the pretargeted receptor, thereby delivering the active agent to the target.
Pretargeting is made more efficient by administration of a clearing agent to facilitate elimination of circulating targeting moiety. Various clearing agents have been disclosed. Galactose-human serum albumin (HSA)-biotin clearing agents have been employed in pretargeting protocols employing a monoclonal antibody-streptavidin targeting moiety and a biotin-active agent construct. Such clearing agents are discussed in PCT/US93/05406. Derivatization by galactose facilitates elimination of complexes of monoclonal antibody-streptavidin-biotin-HSA-galactose via Ashwell receptors in the liver. These clearing agents rapidly decrease circulating monoclonal antibody-streptavidin levels in patients. Since pretargeting methods are enhanced using clearing agents, improvements in such clearing agents are sought.
SUMMARY OF THE INVENTION
The present invention is directed to low molecular weight cluster clearing agents (CCAs) which meet certain performance criteria and are amenable to scale up for commercial production. Preferred CCAs of the present invention preferably exhibit one or more of the following characteristics:
rapid, efficient complexation with serum-associated targeting moiety-ligand (or anti-ligand) conjugate in vivo;
rapid clearance from the blood of serum-associated targeting moiety conjugate capable of binding a subsequently administered complementary anti-ligand or ligand containing molecule;
high capacity for clearing (or inactivating) large amounts of serum-associated targeting moiety conjugate; and
low immunogenicity.
In addition, CCAs of the present invention are preferably capable of achieving circulating targeting moiety clearance without compromising the binding potential of the pretargeted targeting moiety, either directly by binding of the CCA thereto or indirectly by binding of CCA metabolites thereto. The present invention also contemplates CCAs of defined chemistry to facilitate characterization, manufacturing and quality control. The CCAs of this invention are also designed to be effective over a broad dose range to avoid the desirability of extensive dose optimization. The present invention further provides CCAs of increased efficiency in clearance of circulating targeting moiety.
Preferred CCAs of present invention incorporate (1) a cluster hepatic clearance directing moiety; and (2) a binding moiety incorporating a member of a ligand/anti-ligand pair or a lower affinity form thereof. The cluster hepatic clearance directing moiety is composed of a cluster of sugar residues arranged on a cluster backbone and mediates hepatic clearance of the CCA via recognition of the sugar clusters by a hepatocyte receptor. The ligand or anti-ligand binding moiety facilitates binding to targeting moiety-ligand/anti-ligand conjugate. Preferably, CCAs of the present invention range in molecular weight from between about 1,000 and about 20,000 daltons, more preferably from about 2,000 to 16,000daltons. Such preferred CCAs generally incorporate between about 4 and about 32 sugar residues, with about 16 sugar residues more preferred.
More preferred CCAs of the present invention are characterized by one or more of the following:
Unnatural orientation of ligand (e.g., 1-biotin) and anti-ligand (e.g., streptavidin formed from d-amino acids);
Secondary amide connecting a sugar residue to the cluster backbone of the CCA;
High affinity sugar for binding to the Ashwell receptor (e.g., N-acetylgalactosamine);
Orientation for sugar attachment (e.g., alpha-orientation sugar attachment is generally preferred for N-acetylgalactosamine hexoses, and beta-orientation sugar attachment is generally preferred for galactose hexoses);
Appropriate linking atom for sugar attachment (e.g., sulfur linker atoms are generally preferred with regard to metabolic stability of CCAs);
Optimized spacer between the linker atom and the nitrogen atom of the amide connecting the sugar residue to the cluster backbone of the CCA;
Tertiary amine adjacent to the ligand or anti-ligand component to enhance in vivo stability of the CCA; and
Extended linker between the cluster backbone and the ligand or anti-ligand to improve the bioavailability of said ligand or anti-ligand.
CCAs of the present invention may also be employed to remove toxic or potentially toxic moieties from a recipient's circulation or extravascular space. In this embodiment, the CCA comprises a hepatic clearance directing moiety and a binding moiety capable of recognizing a component or an epitope associated with the toxic or potentially toxic moieties.
Another embodiment of the present invention is a CCA-protein clearing agent. For example, HSA may be derivatized with one or more CCAs, preferably 1 or 2 CCAs, and optionally derivatized by hexose residues. By virtue of the synthetic nature of the CCA and the methylated amide bond(s) incorporated in the linker/extender between the cluster and their binding moiety, the CCA is resistant to metabolic degradation. Consequently, any CCA-biotin metabolites of this proteinaceous clearing agent are likely to be retained n liver hepatocytes.
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Axworthy Donald B.
Theodore Louis J.
Duffy Patricia A.
NeoRx Corporation
Seed Intellectual Property Law Group PLLC
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