Anti-mesothelin antibodies

Inventors

Ebel, Wolfgang • Grasso, Luigi • Nicolaides, Nicholas C. • Sass, Philip M. • Routhier, Eric

Assignees

Eisai Inc

Abstract

This invention relates to the use of monoclonal and polyclonal antibodies that specifically bind to and become internalized by mesothelin-positive cells and also induce an immune effector activity such as antibody dependent cellular cytotoxicity. The antibodies are useful in specific delivery of pharmacologic agents to mesothelin expressing cells as well as eliciting an immune-effector activity particularly on tumor cells and precursors. The invention is also related to cells expressing the monoclonal antibodies, polyclonal antibodies, antibody derivatives, such as human, humanized, and chimeric monoclonal antibodies, antibody fragments, mammalian cells expressing the monoclonal antibodies, derivatives and fragments, and methods of treating cancer using the antibodies, derivatives and fragments.

Core Innovation

The disclosed invention relates to anti-mesothelin “in-out” antibodies that bind mesothelin on mesothelin-positive tumor cells and that either elicit immune effector activity and/or internalize after binding. The document positions these antibodies as improving upon prior mesothelin antibody approaches such as mAb K1/SS1 by addressing limitations in internalization and/or immune effector function. The antibodies are described as distinguishing from K1/SS1 by improved affinity/avidity, robust immune effector activity, and/or internalization.

The document provides methods for determining the presence of mesothelin-positive cells in a biological sample and in a subject by detecting binding of an antibody that binds mesothelin. In these methods, the antibody is defined by heavy chain variable domain and light chain variable domain amino acid sequence requirements using SEQ ID NO: 2/6/10 for heavy chains and SEQ ID NO: 4/8/12 for light chains (with amino acids 1 to 19 absent). Binding of the antibody to the biological sample or mesothelin-positive cell indicates the presence of the mesothelin-positive cell.

The document also describes pharmaceutical compositions comprising a mesothelin-binding antibody defined by the same SEQ ID NO-based heavy and light chain variable domain sequences and further includes that the antibody is labeled with a detectable label. The described detectable labels include categories and specific named examples such as enzyme, radioactive, fluorescent, and chromophoric labels, including Indium-111 and In-DOTA. The document further frames these antibodies and labeled formats within cancer detection and treatment concepts.

Claims Coverage

The provided independent claims cover three main aspects: (i) determining the presence of mesothelin-positive cells in a biological sample using an antibody with specified SEQ ID NO heavy/light variable-domain sequences, (ii) determining the presence of mesothelin-positive cells in a subject via detecting mesothelin-binding, and (iii) pharmaceutical compositions of such mesothelin-binding antibodies labeled with a detectable label. Across these, the antibody binding/sequence definition is central, with inventive features also focusing on the detection context and labeled compositions.

Overall, the claim coverage centers on mesothelin-binding antibodies defined by specific heavy and light chain variable domain sequence constraints (SEQ ID NO: 2/6/10 for heavy and SEQ ID NO: 4/8/12 for light, with amino acids 1 to 19 absent). These antibodies are used for binding-based detection of mesothelin-positive cells in biological samples and in subjects, and they are also formulated as labeled pharmaceutical compositions.

Stated Advantages

Documented Applications