Therapeutic constructs for co-delivery of mitotic kinase inhibitor and immune checkpoint inhibitor

Inventors

Yantasee, Wassana • REDA, Moataz • NGAMCHERDTRAKUL, Worapol

Assignees

Oregon Health and Science University • PDX Pharmaceuticals Inc

Abstract

Disclosed herein are therapeutic constructs including a delivery particle, at least one mitotic kinase inhibitor, and at least one immune checkpoint inhibitor. Also disclosed are therapeutic constructs including a mitotic kinase inhibitor, an immune checkpoint inhibitor, and a chemical linker. These therapeutic constructs cause cancer death by both therapeutic and immune effects and promote targeted delivery of more therapeutics to the surviving cancer cells in a positive feed-back loop. They enhance therapeutic index of free drugs and can be used intratumorally or systemically. This strategy can treat broad cancer types and is particular useful for cancer without obvious receptors for cancer-targeted delivery of otherwise toxic therapeutics.

Core Innovation

The disclosure describes cancer immunotherapy therapeutic constructs comprising a mesoporous silica nanoparticle (MSNP) platform loaded with a small molecule Polo-like Kinase (PLK1) inhibitor or a PLK1 siRNA. The constructs further include a Programmed Death-Ligand 1 (PD-L1) antibody conjugated onto the MSNP platform. In another aspect, the MSNP platform comprises 0.01% to 5% mitotic kinase inhibitor by weight of the therapeutic construct, together with an antibody against PD-L1 conjugated onto the MSNP platform.

The constructs are presented as therapeutic constructs that combine mitotic-cell death induction with immune checkpoint targeting in the same construct. The disclosure links mitotic-cell death induction to checkpoint modulation, so that a checkpoint antibody on the construct can home to and enhance cytotoxic T-cell attack, and potentially establish a feed-forward adaptive immune loop. The combined delivery concept is presented together with PD-L1 blockade and mitotic kinase inhibition to support tumor growth control and associated immune effects such as T cell infiltration.

The disclosure further states that the mitotic kinase inhibitor can be a PLK1 inhibitor, including examples such as volasertib and alisertib, or PLK1 siRNA. The problem described is the need for cancer immunotherapy that can induce mitotic-cell death while enabling immune checkpoint blockade activity from the same construct. The constructs are positioned to improve therapeutic index compared with free drugs and to support broader cancer-type coverage.

Claims Coverage

The independent claims identify three main inventive construct variants: an MSNP loaded with a small molecule PLK1 inhibitor plus PD-L1 antibody conjugation with a 0.01% to 5% by-weight constraint, an MSNP loaded with a mitotic kinase inhibitor plus PD-L1 antibody conjugation with the same 0.01% to 5% by-weight constraint, and an MSNP platform comprising PLK1 siRNA plus PD-L1 antibody conjugation. Across these independent claims, the core inventive features are the MSNP platform with the specified mitotic kinase payload and the PD-L1 antibody conjugation.

The claim set is centered on PD-L1 antibody-conjugated MSNP platforms that co-present mitotic kinase inhibition payloads, either as a small molecule PLK1 inhibitor, as mitotic kinase inhibitor more generally, or as PLK1 siRNA. The independent claims explicitly constrain payload content to 0.01% to 5% by weight for the small molecule/mitotic kinase-inhibitor variants, while the PLK1 siRNA variant is characterized by the presence of PLK1 siRNA on the MSNP platform with PD-L1 antibody conjugation.

Stated Advantages

Documented Applications