Looking at PD-(L)1×TGF-β from ESMO in 2021

In 2021, ASCO announced the Phase I clinical data of SHR-1701 for solid tumors and EGFR-mutant NSCLC
.
As of October 30, 2020, 49 patients with evaluable solid tumors received 6 weeks of SHR-1701 treatment, ORR was 17.
8%, DCR was 40%, and mDoR was not reached; 24 patients with evaluable NSCLC tumors received 8.
7 weeks of SHR- With 1701 monotherapy, the ORR was 16.
7%, the DCR was 50%, and the TRAE rate above grade 3 was 7.
4%, including anemia, hypokalemia, etc.
, without grade 4-5 TRAE
.
In general, in the two trials, patients used SHR-1701 for a shorter period of time.
The data disclosed by ASCO lacked key DoR data.
The evaluation of the drug still needs more data disclosure
.

(3) Y101D is a bifunctional fusion antibody targeting PD-L1 and TGF-β developed by Friends of Zhiyou using the independent patented quadrivalent symmetric bispecific antibody CHECKBODY platform
.
In January 2021, it was approved by the FDA to conduct clinical trials, and then in February, it received NMPA to conduct clinical trials for solid tumors
.

From the structural point of view, Y101D has a special structure, its binding TGF-β end is the Fv structure of anti-TGF-β antibody, and M7824 targeting TGF-β end is the extracellular region of the receptor TGFBRII
.
Pre-clinical pharmacy studies have shown that: Y101D antibody candidate drug has high expression, good stability, simple sugar type, and has shown significant tumor suppression effects in a variety of mouse tumor models
.

Picture: Y101D structure

Data source: Youzhiyou Bio

(4) PM8001 is the first bispecific antibody of Promis Biosciences, which was approved by the NMPA for clinical trial of drugs in March 2020
.
From the structural point of view, PM8001 is similar to M7824.
The N-terminus can recognize the antibody structure that binds to PD-L1, and the C-terminus can bind to the TGF-β receptor type II fusion protein of TGF-β; it does not contain a light chain structure, and there is no light or heavy Chain mismatch problem; and the molecular weight is small, and the ability to penetrate solid tumors is strong
.

In March 2020, Pumis and Maiwei Biotechnology signed a strategic cooperation agreement to establish a joint venture company in Zhuhai to carry out clinical research, commercial production and sales of PM8001 in Greater China
.

Picture: PM8001 structure

Data source: Pumis Bio

(5) QLS31901 is a PD-L1×TGF-β bispecific antibody of Qilu Pharmaceutical, which can simultaneously block the PD-L1 and TGF-β pathways, improve the tumor microenvironment, and promote the killing of tumor cells by immune cells
.
QLS31901 was approved for clinical use in March 2021
.
On June 2, QLS31901 completed the first patient administration
.

Figure: QLS31901 mechanism of action

Data source: Qilu.
com

03 Summary

Based on the early bright data of M7824, a group of domestic pharmaceutical companies have deployed the target combination of PD-L1×TGF-β, including Hengrui Pharmaceuticals, Promis Biosciences, Qilu Pharmaceuticals, and Youzhiyou
.
According to incomplete statistics, the number of domestic companies in the clinical stage for this target combination is close to 10, and there are more than 10 companies in the pre-clinical stage
.
In addition, Junshi Bio and Weilizhibo have deployed PD-1×TGF-β double antibodies
.

Under the layout of so many companies, the risks and opportunities of this target combination coexist.
On the one hand, no drug for PD-(L)1×TGF-β has been approved for listing yet, and M7824 is frequently declining, and the risk of research and development is high; on the other hand, On the one hand, drug R&D tends to be homogeneous.
Even if R&D is successful, commercialization may face fierce competition
.

Of course, it may be too early to discuss commercial competition at this stage.
Successful R&D and accelerated listing are the top priorities for every PD-(L)1×TGF-β enterprise
.