Anti-CD137 antigen-binding molecule and utilization thereof

Inventors

Igawa, Tomoyuki • Sakurai, Mika • Shimizu, Shun • Hori, Yuji • Hironiwa, Naoka • SAVORY, Nasa • Narita, Yoshinori • KAMIKAWA, TAKAYUKI • Miyazaki, Taro • Kadono, Shojiro • Hasegawa, Masami • Tatsumi, Kanako • Hayasaka, Akira • KAWAI, Takeaki • Mimoto, Futa • KAWAUCHI, Hiroki • Kamimura, Masaki

Assignees

Chugai Pharmaceutical Co Ltd

Abstract

An objective of the present disclosure is to provide anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, and methods of using the same.Anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, are provided by discovering and producing CD137 antigen-binding molecules whose binding activity to CD137 depends on various substances (for example, small molecule compounds) in target tissues. Methods of using the same, pharmaceutical formulations, and such are also provided.The present disclosure also provides an antigen-binding molecule whose binding activity to an antigen varies depending on a small molecule compound, a preparation method thereof, and uses thereof.

Core Innovation

The disclosure describes anti-CD137 antigen-binding molecules and anti-CD137 antibodies defined by combinations of HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 selected from enumerated options, together with defined heavy chain variable and light chain variable domains and constant regions. It further includes altered Fc region variants for human FcγR binding and human FcRn binding, and the partial content also describes switch antibodies whose CD137 binding and agonist activity depend on small molecules, including ATP/ADP/AMP and kynurenine-dependent behavior.

The described work evaluates anti-CD137 antigen-binding molecules in human CD137 knock-in mice, including plasma pharmacokinetics and half-life measurement criteria. It addresses switch molecule/switch antibody versus non-switch antibody behavior, including reduced switch off-target binding, improved kinetics, prolonged blood half-life, and reduced systemic T-cell activation, with systemic reaction and immune activation readouts in liver, spleen, and lymph nodes using markers such as granzyme B, PD-1, ICOS, and immune cell ratios.

The document further expands to immunoconjugates/antibody-drug conjugates and includes in vivo anti-tumor efficacy testing in xenograft and syngeneic models, including an MC38 cell line model. It also describes CD137 detection and patient selection using labeled antibodies and diagnostics/detection use cases, and further characterizes antigen-binding activity using reported binding parameters, FcγR binding and FcRn binding, and functional activities such as ADCC, ADCP, CDC, and neutralizing activity.

Claims Coverage

The independent claim coverage centers on sequence-defined anti-CD137 antigen-binding molecules through specified HVR-region combinations, an antibody defined by fixed VH and VL SEQ ID NOs, altered Fc-region substitutions, and a method for treating a solid tumor infiltrated by CD137-expressing immune cells by administering the anti-CD137 antigen-binding molecule. Four inventive features are identified.

The claim coverage is concentrated on anti-CD137 binders defined by enumerated HVR-region combinations and fixed VH/VL sequence identifiers, with additional claim themes directed to altered Fc-region substitutions and treatment of solid tumors infiltrated by CD137-expressing immune cells.

Stated Advantages

Documented Applications