Neorx Corporation

Vivekananda M Vrudhula

Ananthachari Srinivasan

Mark D Hylarides

Jeffrey N Fitzner

Diana I Brixner

Paul G Abrams

A Charles Morgan, Jr

Gowsala P Sivam

The present invention provides cleavable conjugates whose linkers contain a labile bond that is cleavable under a variety of mild conditions, including weakly acidic. Since the agent may be bonded directly to the linker, cleavage can result in release of native agent. The invention also provides methods for producing cleavable conjugates. Preferred agents include drugs, toxins, biological response modifiers, radiodiagnostic compounds, radiotherapeutic compounds, and derivatives thereof. The targeting molecule employed in the invention may be an intact molecule, a fragment thereof, or a functional equivalent thereof. In a particularly preferred embodiment, the targeting molecule is a monoclonal antibody directed towards a tumor-associated antigen in man. The invention further provides methods for delivering to the cytoplasm of a target cell an agent free of its targeting molecule carrier. A diagnostically/therapeutically effective dose of a cleavable conjugate is administered to a warm-blooded animal such as man.

Cleavable conjugates for the delivery and release of agents in native

A chemically defined polymeric carrier comprising a series of .alpha.-amino acids in any combination containing side chains to which diagnostic/therapeutic and chelating agents can be covalently joined through cleavable linkers either directly or covalently joined through cleavable linkers after chemical modification of the side chains. Hydrazone, disulfide, and ester linkages in any combination can be present in the polymeric carrier between the side chains of the .alpha.-amino acids and the agents. The presence of a particular covalent linkage between the side chain and the agent in the carrier is determined by the functional group present in the side chain of the .alpha.-amino acid and the functional group present in the agent. The .alpha.-amino acids with side chains to which agents do not covalently join can function as spacers to minimize interaction between bulky molecules attached to the polymeric carrier. In addition, those .alpha.-amino acids with charged or hydrophilic side chains to which agents do not covalently join can provide increased solubility to the polymeric carrier.

Chemically defined polymeric carriers for release of covalently linked

Targeting substance-diagnostic/therapeutic agent conjugates joined by stabilized Schiff base or hydrazone linkages are disclosed. In addition, slow release carrier-drug pharmaceuticals are described. The diagnostic and therapeutic conjugates and pharmaceuticals of the present invention provide certain advantages relating to in vivo administration, including controlled release of the active agent at a target site.

Targeting substance-diagnostic/therapeutic agent conjugates having

The present invention provides cleavable conjugates whose linkers contain a labile bond that is cleavable under a variety of mild conditions, including weakly acidic. Since the agent may be bonded directly to the linker, cleavage can result in release of native agent. The invention also provides methods for producing cleavable conjugates. Preferred agents include drugs, toxins, biological response modifiers, radiodiagnostic compounds, radiotherapeutic compounds, and derivatives thereof. The targeting molecule employed in the invention may be an intact molecule, a fragment thereof, or a functional equivalent thereof. In a particularly preferred embodiment, the targeting molecule is a monoclonal antibody directed towards a tumor-associated antigen in man. The invention further provides methods for delivering to the cytoplasm of a target cell an agent free of its targeting molecule carrier. A diagnostically/therapeutically effective dose of a cleavable conjugate is administered to a warm-blooded animal such as man. Another aspect of the invention provides methods for isolating a compound. The compound binds covalently to a solid phase which has been derivatized with the linkers described above and is released in native form by a variety of mild conditions. An additional aspect of the invention provides methods for introducing into a compound a free sulfhydryl, amino, or hydroxyl group by use of reagents structurally related to the linkers described above. Preferred uses of the method are to add a free amino or a free sulfhydryl group to a protein, such as an antibody, or a drug.

Methods for isolating compounds using cleavable linker bound matrices

The activity of cytotoxic agents on target cells is enhanced through administration of a sensitizing agent to a patient prior to or simultaneously with administration of the cytotoxic agent. One or both of the two types of agents are attached to antibodies specific for the desired target cells, thereby enhancing the cytotoxic effect on target cells compared to non-target cells. The sensitizer and/or the cytotoxic agent may be attached to monoclonal antibodies specific for cancer cells to selectively eradicate the cancer cells while minimizing toxicity toward normal tissues.

Method of enhancing the effect of cytotoxic agents

The present invention provides cleavable conjugates whose linkers contain a labile bond that is cleavable under a variety of mild conditions, including weakly acidic. Since the agent may be bonded directly to the linker, cleavage can result in release of native agent. The invention also provides methods for producing cleavable conjugates. Preferred agents include drugs, toxins, biological response modifiers, radiodiagnostic compounds, radiotherapeutic compounds, and derivatives thereof. The targeting molecule employed in the invention may be an intact molecule, a fragment thereof, or a functional equivalent thereof. In a particularly preferred embodiment, the targeting molecule is a monoclonal antibody directed towards a tumor-associated antigen in man. The invention further provides methods for delivering to the cytoplasm of target cell an agent free of its targeting molecular carrier. A diagnostically therapeutically effective dose of a cleavable conjugate is administered to a warm-blooded animal such as man. Another aspect of the invention provides methods for isolating a compound. The compound binds covalently to a solid phase which has been derivatized with the linkers described above and is released in native form by a variety of mild conditions. An additional aspect of the invention provides methods for introducing into a compound a free sulfhydryl, amino, or hydroxyl group by use of reagents structurally related to the linkers described above. Preferred uses of the method are to add a free amino or a free sulfhydryl group to a protein, such as an antibody, or a drug.

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Edmonds, WA, United States of America

Vivekananda M Vrudhula