Regeneron Pharmaceuticals, Inc.

Irene Noguera-Troise

Gavin Thurston

Eric L Smith

Nicholas J Papadopoulos

Joel H Martin

Alain Thibault

Nicholas W Gale

Eric Smith

The present invention provides methods of treating, ameliorating, or inhibiting tumor growth, cancer, or pathological angiogenesis by administering to a subject in need thereof a human antibody or fragment thereof that specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The anti-hDll4 antibody or fragment thereof of the present invention have a high affinity with the Kof 500 pM or less, as measured by surface plasmon resonance.

Human antibodies to human delta like ligand 4

The invention provides methods for treating various types of cancer/tumor by administering the combination of Dll4 antagonists, in particular, Dll4 antibodies and fragments thereof that specifically bind human Dll4, and chemotherapeutic agents. Such combination therapies exhibit synergistic effects compared to the treatment with either agent alone. Thus, the methods of the invention are particularly beneficial for cancer patients who have low tolerance to the side effects caused by high dosages required for the treatment by either agent alone, by being able to reduce effective dosages. Pharmaceutical compositions and kits containing Dll4 antagonists and chemotherapeutic agents are also provided.

Method of treating cancer with DLL4 antagonist and chemotherapeutic agent

Disclosed is a therapeutic method for inhibiting development or growth of tumors that are resistant to the blockade of delta-like ligand 4 (Dll4), or vascular endothelial growth factor (VEGF), or to other therapeutic agents, by administering the combination of Dll4 antagonist and VEGF antagonist. The combined administration of these two agents, concurrently or sequentially, exhibits synergistic effects on blood vessel development and growth, thereby more effectively inhibiting the tumor growth than an administration of either agent alone. The Dll4 antagonist can be an anti-Dll4 antibody or antibody fragment capable of inhibiting the binding of Dll4 to a Notch receptor, or a fusion protein comprising the extracellular domain of Dll4 or a soluble Notch receptor, or a fragment thereof, fused to a multimerizing component. The VEGF antagonist can be a VEGF trap, anti-VEGF antibody or antibody fragment capable of inhibiting the binding of VEGF to a VEGF receptor.

Therapeutic methods for inhibiting tumor growth with combination of Dll4 antagonists and VEGF antagonists

An isolated human antibody or a fragment of a human antibody which specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The human anti-hDll4 antibody or antibody fragment binds hDll4 with an affinity of &#x2266;500 pM, as measured by surface plasmon resonance.

An isolated human antibody or a fragment of a human antibody which specifically binds to human delta-like ligand 4 (hDII4) and blocks hDII4 binding to a Notch receptor. The human anti-hDII4 antibody or antibody fragment binds dimeric hDII4 with an affinity of 75 pM or better, as measured by surface plasmon resonance.

An isolated human antibody or a fragment of a human antibody which specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The human anti-hDll4 antibody or antibody fragment binds hDll4 with an affinity of 300 pM or better, as measured by surface plasmon resonance.

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Bay Shore, NY, United States of America

Irene Noguera-Troise