Serious involution of PD-1?

The immune system plays an important role in controlling and eradicating tumors, however, tumor cells can often evade or suppress immune responses

Therapeutic antibodies targeting PD-L1 or PD-1 have been proven to be effective treatments for a variety of tumors, and more than 10 PD-1/PD-L1 immune checkpoint inhibitors have been approved for marketing at home and abroad

PD-1/PD-L1 checkpoint inhibitor approval schedule (Source: Nat Rev Drug Discov.

Compared with therapeutic antibodies, small molecule PD-L1/PD-1 inhibitors have the unique advantage of having a shorter half-life, allowing flexible timing and dose adjustment to minimize immune-related adverse events and maximize Benefit/risk ratio

With the in-depth study of PD-L1 and PD-1 crystal structures, the revealing of key amino acids (hot-spots) at the PD-L1/PD-1 interaction interface can be used to guide the design of small molecule inhibitors

Peptidyl PD-L1/PD-1 small molecule inhibitor (Source: Acta Pharmacol Sin.

In 2015, BMS began to focus on the development of non-peptide PD-L1/PD-1 small molecule inhibitors, and companies such as Incyte and Polaris subsequently joined the ranks, and corresponding candidate compounds entered the early clinical stage

Non-peptide PD-L1/PD-1 small molecule inhibitor (Source: Acta Pharmacol Sin.

On March 7, 2022, Incyte researchers reported a small molecule inhibitor of PD-L1, INCB086550, in the journal Cancer Discovery, which has similar biological properties to PD-L1/PD-1 monoclonal antibodies , may represent an alternative to antibody therapy

Source: Cancer Discovery

INCB086550 Structure

HTRF-based PD-L1/PD-1 molecular level binding experiments found that INCB086550 can bind to human, cynomolgus monkey and rat PD-L1 proteins, but the binding ability to mouse PD-L1 proteins is weak (protein amino acid sequence differences)

Activity data for the small molecule PD-L1 inhibitor INCB086550

Next, the researchers used a variety of antibodies to characterize the effect of INCB086550 on the formation and internalization of PD-L1 dimers

INCB086550 induces the formation and internalization of PD-L1 dimers

We then evaluated the effects of INCB086550 on PD-1 signaling and immune activation at the cellular level

PD-1/PD-L1 Blockade Bioassay

The pharmacokinetic/pharmacokinetic data for INCB086550 are favorable

Tumor/plasma distribution of INCB086550

Further evaluation of in vivo antitumor activity in a humanized mouse model showed that INCB086550 significantly inhibited the tumor growth of MC38 huPD-L1 in an immune-sound mouse model, but was ineffective in immunodeficient mice, indicating that the antitumor efficacy of INCB086550 was dependent on for immunity

In vivo antitumor activity of INCB086550

Finally, in an ongoing Phase 1 study, researchers assessed active pharmacodynamic markers, including INCB086550 binding to PD-L1, downstream markers of the IFNγ pathway, and levels of cell-free PD-L1

Changes in clinical test indicators

Excitingly, although there have been previous reports of small molecule immune checkpoint inhibitors, this is the first time to reveal complete preclinical data on a druggable small molecule inhibitor that can block the PD-1/PD-L1 interaction and preliminary clinical data

Incyte's tumor immunotherapy product pipeline source: Incyte official website

According to public information, Incyte is still developing anti-PD-1 monoclonal antibody Retifanlimab, and two other PD-L1 small molecule drugs, INCB99280 and INCB99318, are also in the preclinical development stage
.

references:

[1] Li, Guanqiao et al.
“Comparing development strategies for PD1/PDL1-based immunotherapies.
” Nature reviews.
Drug discovery, 10.
1038/d41573-022-00003-7.

[2] Koblish, Holly K et al.
“Characterization of INCB086550, a potent and novel small-molecule PD-L1 inhibitor.
” Cancer discovery, 10.
1158/2159-8290.
CD-21-1156

[3] Wu, Qian et al.
“Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway.
” Acta pharmacologica Sinica, 10.
1038/s41401-020-0366-x

[4] Fattakhova, Elena et al.
“Identification of the FDA-Approved Drug Pyrvinium as a Small-Molecule Inhibitor of the PD-1/PD-L1 Interaction.
” ChemMedChem, 10.
1002/cmdc.
202100264