Methods of using bispecific molecules having immunoreactivity with PD-1 and CTLA-4

Inventors

Johnson, Leslie S. • Chichili, Gurunadh Reddy • Shah, Kalpana • La Motte-Mohs, Ross • Moore, Paul A. • Bonvini, Ezio • Koenig, Scott

Assignees

Macrogenics Inc

Abstract

The present invention is directed to bispecific molecules (e.g., diabodies, bispecific antibodies, trivalent binding molecules, etc.) that possess at least one epitope-binding site that is immunospecific for an epitope of PD-1 and at least one epitope-binding site that is immunospecific for an epitope of CTLA-4 (i.e., a “PD-1×CTLA-4 bispecific molecule”). The PD-1×CTLA-4 bispecific molecules of the present invention are capable of simultaneously binding to PD-1 and to CTLA-4, particularly as such molecules are arrayed on the surfaces of human cells. The invention is directed to pharmaceutical compositions that contain such PD-1×CTLA-4 bispecific molecules, and to methods involving the use of such bispecific molecules in the treatment of cancer and other diseases and conditions. The present invention also pertains to methods of using such PD-1×CTLA-4 bispecific molecules to stimulate an immune response.

Core Innovation

The invention relates to PD-1×CTLA-4 bispecific immunoreactive binding molecules that simultaneously bind PD-1 and CTLA-4. The bispecific molecules are presented in multiple molecular formats including diabodies, bispecific antibodies, and trivalent binding molecules, with polypeptide-chain compositions defined by SEQ ID NOs. The described bispecific compositions include embodiments that contain Fc region or Fc-containing variants.

The molecules are organized as multichain constructs including constant region elements such as CL, CH1, hinge, and Fc. The Fc region is engineered to modulate effector function, including reducing or increasing FcγR binding, and to extend serum half-life via Fc substitutions. The constructs are further described with constant-region variant selection to tune Fc-mediated activity while maintaining the bispecific trivalent binding functionality.

The invention also addresses diseases and conditions associated with a suppressed immune system by administering an amount effective to treat the disease or condition. It also includes methods for stimulating an immune-mediated response by administering an amount effective to stimulate the immune-mediated response. The overall concept is to enhance immune stimulation and enhance potency while reducing immune-related adverse effects.

Claims Coverage

The provided claim set includes independent methods directed to treating a disease or condition associated with a suppressed immune system and stimulating an immune-mediated response. Across the independent claims, the inventive features are the specified PD-1×CTLA-4 bispecific molecule chain compositions and amount-effective administration.

The claim coverage focuses on methods of treating suppressed-immune diseases and methods of stimulating immune-mediated responses using PD-1×CTLA-4 bispecific molecules defined by SEQ ID NO-based polypeptide-chain compositions. The independent claim set distinguishes different bispecific chain configurations.

Stated Advantages

Documented Applications