4-1BB binding molecules

Inventors

AHRENS, Bianca • BAXI, Sangita M. • Fisher, Timothy Scott • JEROME, Richard Michael • Ladetzki-Baehs, Kathrin • Oliphant, Theodore • SHARP, Leslie Lynne • Tesar, Michael • YATES, Libbey Anne • ZULLEY, Moritz

Assignees

Pfizer Inc

Abstract

The present disclosure provides isolated binding molecules that bind to human 4-1BB, nucleic acid molecules encoding an amino acid sequence of the binding molecules, vectors comprising the nucleic acid molecules, host cells containing the vectors, methods of making the binding molecules, pharmaceutical compositions containing the binding molecules, and methods of using the binding molecules or compositions.

Core Innovation

The invention provides isolated human 4-1BB binding molecules, including an isolated antibody or an antigen-binding portion thereof, that binds the human 4-1BB extracellular domain at an epitope located within amino acid residues 115-156 of SEQ ID NO:68. The binding molecules include fully human antibodies and antigen-binding fragments, and include antibodies defined by specific CDR compositions with described H-CDR1/2/3 and L-CDR1/2/3 sequences using multiple SEQ ID variants.

The disclosed molecules are characterized by binding to the defined 4-1BB epitope with stated affinity ranges determined using BIACore/BIAcore assays, including KD thresholds down to ≤600 nM and further to ≤450 nM in the disclosed ranges. The document further describes selectivity against CD40 and CD134, and provides additional functional characterization including agonist activity assessed using NF-κB luciferase reporter activity and IL-2 release.

The invention also encompasses nucleic acids encoding the antibodies or antigen-binding portions, vectors, and host cells for expression, and pharmaceutical compositions comprising the antibodies with a pharmaceutically acceptable carrier, including glycosylation-content constraints. Therapeutic uses are described in connection with treatment of cancer contexts, including tumor metastasis and abnormal cell growth, as well as immune enhancement and autoimmune and inflammatory disease contexts.

Claims Coverage

The provided claim set centers on an isolated antibody or antigen-binding portion that binds human 4-1BB extracellular domain at a defined epitope, with multiple dependent claims refining affinity by surface plasmon resonance threshold, VH and VL sequence definition, and therapeutic method scope. In total, the inventive features group around epitope binding specificity, binding affinity, sequence specification, and cancer treatment using a pharmaceutically acceptable carrier, with combination use of rituximab also recited.

The claims are directed to antibodies that bind the human 4-1BB extracellular domain at an epitope within residues 115-156 of SEQ ID NO:68, with further limitations on binding affinity, VH/VL sequence definition, and therapeutic methods for treating cancer in a mammal using a therapeutically effective amount with a pharmaceutically acceptable carrier. Additional claim features specify certain cancer types and include rituximab.

Stated Advantages

Documented Applications