Professor Shen Lin: TGF-β and PD-(L)1 join forces, and a new generation of antibodies is coming?

*Only for medical professionals to read for reference.
Hengrui's Phase I study of bispecific antibodies targeting PD-L1 and TGF-β appeared in ASCO’s oral report
.

Bispecific antibodies are one of the hotspots of drug development in the oncology field.
Unlike monoclonal antibodies that bind to a single specific epitope, bispecific antibodies are artificially engineered antibodies that can simultaneously bind to two specific epitopes or target proteins.
Thereby, many monoclonal antibody drugs or combination drugs can not have the treatment effects of diseases
.

In the 2021 American Society of Clinical Oncology (ASCO) conference "R&D stage therapy-immunotherapy" special session, a "targeting PD-L1 and TGF-β (transforming growth factor β) dual-function fusion protein SHR-1701 "Phase I study for the treatment of patients with advanced solid tumors" will be reported orally
.

"Medical Oncology Channel" is fortunate to invite the corresponding author of the study, Professor Lin Lin from Peking University Cancer Hospital, to interpret the important results of the study and the development prospects of bispecific antibodies in the field of oncology
.

Figure 1: Screenshot of 2503 oral report research.
TGF-β is involved in the occurrence and development of tumors.
Professor Lin Shen introduced, “SHR-1701 is a fusion protein that targets PD-L1/TGF-β dual functions developed by Hengrui.
This is what we often call "double antibodies" (bispecific antibodies)
.

The study published by ASCO this time is a phase I study to evaluate the safety and preliminary anti-tumor activity of SHR-1701 in refractory solid tumors
.

The research is currently in progress, and it is in the stage of dose climbing and population expansion
.

A phase I study was submitted to ASCO as an oral presentation, which shows that everyone is paying more attention to the bifunctional fusion protein
.

"Professor Shen pointed out, "The anti-tumor onset mechanism that targets the PD-L1 pathway is already familiar and understood clinically, while the familiarity of TGF-β is not so high
.

TGF-β acts as a growth inhibitor in the early stage of tumorigenesis.
After the tumor grows to a certain extent, TGF-β will act as a stimulating factor to promote tumor growth
.

Therefore, TGF-β plays an important role in the occurrence and development of tumors
.

"TGF-β-mediated signal transduction in the tumor microenvironment can promote tumor invasion, migration and metastasis through a variety of mechanisms including epithelial cell-to-mesenchymal transition (EMT) [1]
.

TGF-β in cancer and including cancer It is expressed in interstitial cells including related fibroblasts (CAFs)
.

TGF-β can maintain tumor progression by activating CAFs, stimulating immune suppression and promoting vascular factors [2]
.

PD-1/PD-L1 and TGF-β The pathway has independent and complementary immunosuppressive functions[3-5]
.

Therefore, if drugs can block the two immune signaling pathways of TGF-β and PD-L1 at the same time, it can further improve anti-tumor activity and efficacy
.

Figure 2: Research Background The preliminary results of SHR-1701 were announced, with ORR 17.
8% and DCR reaching 40%.
The dose escalation phase of this phase I study was started by accelerated titration (1 mg/kg Q3W), and then switched to the 3+3 regimen (3 mg/kg).
, 10 mg/kg, 20 mg/kg, 30 mg/kg Q3W and 30 mg/kg Q2W)
.

The dose was expanded at 10 mg/kg, 20 mg/kg, 30 mg/kg Q3W, and 30 mg/kg Q2W
.

The main purpose is to determine the safety, tolerability, maximum tolerated dose (MTD) and phase II clinical study recommended dose (RP2D) of SHR-1701
.

Figure 3: Study design 17 patients were included in the dose-escalation cohort.
Dose-limiting toxicity (DLT) has not been observed and MTD has not been achieved
.

Another 32 patients were included in the dose expansion cohort
.

The median exposure time of the drug is 6.
0 weeks (range, 2.
0-78.
6), and from the current data, SHR-1701 has not produced new adverse reactions and is safe
.

The most common treatment-related adverse reactions (TRAE) are elevated ALT/AST, anemia, hypothyroidism, and elevated bilirubin/conjugated bilirubin, with an incidence of >15%
.

Figure 3: Basic patient situation Figure 4: Safety results of the study According to the results currently published by ASCO, PK analysis shows that SHR-1701 has a linear relationship with dose exposure in the dose range of 1-30 mg/kg
.

Peripheral blood PD-L1 target occupancy rate in all dose groups exceeded 90%, and TGF-β1 was almost completely trapped
.

Of 49 patients, 45 patients completed at least one efficacy evaluation
.

The objective response rate (ORR) was 17.
8% (95% CI, 8.
0%-32.
1%)
.

8 patients achieved partial remission (PR) [2 cases of lung adenocarcinoma, 1 case of liver cancer, 1 case of esophageal squamous cell carcinoma, 1 case of mismatch repair defect (dMMR) colorectal cancer, 1 case of kidney cancer, 1 case of perineal cancer, 1 case Case of pancreatic acinar cell carcinoma]
.

The disease control rate (DCR) was 40.
0% (18/45; 95% CI, 25.
7%-55.
7%)
.

87.
5% (7/8) of patients are still responding, and the median duration of response (DoR) has not been reached yet
.

Based on safety, PK, PD and efficacy data, the study recommends SHR-1701 30mg/kg Q3W as RP2D
.

Figure 5: Looking at the tumor response on a global scale, Merck’s Bintrafusp alfa (M7824) is the first bifunctional fusion protein targeting PD-L1 and TGF-β to enter clinical studies.
M7824 is due to the human papilloma virus (HPV) related cancers, cholangiocarcinoma (BTC), gastric cancer and other refractory cancers have shown good anti-cancer activity, and were once high hopes for the second-generation "PD-1"
.

But recently, due to the unsatisfactory interim analysis data, Merck announced that it has terminated the Phase III clinical study of the PD-L1/TGF-β anti-M7824 lung cancer
.

Therefore, Professor Shen emphasized, “Based on the current phase I data, we can conclude that SHR-1701 is a bispecific antibody worth exploring.
The initial efficacy is considerable and the safety is good
.
In the
future, SHR-1701 will be in the future.
Can it be applied in clinical practice? In which tumor types can it exert its effect? ​​Can its curative effect surpass traditional monoclonal antibodies? These are still unknown at present
.

With the gradual expansion of the sample size in the future, the dose design and expansion of the phase I study The results of the cohort, as well as the results of related international studies, may be planned for further research and exploration in digestive system tumors
.

Moreover, we believe that this double antibody has the potential to solve some of the PD-1/PD-L1 monoclonal antibody immunity People with poor response, such as biliary tract tumors, pancreatic cancer, and so on
.

"In addition, our study was selected as an oral report by ASCO.
The first is to show that the ability of Chinese pharmaceutical companies is seen internationally; the second is to prove that the previous data of SHR-1701 is comparable to similar products in the world; Third, bispecific antibodies are indeed another major trend in clinical drug research and development, and the future can be expected
.

"Expert Profile Professor Lin Shen, Deputy Dean of Peking University Cancer Hospital, Deputy Director of Beijing Cancer Institute, Director of Gastroenterology Oncology Department, Director of Phase I Clinical Trial Ward, Asian Gastric Cancer Diagnosis and Treatment Guidelines and GIST Diagnosis and Treatment Guidelines Chinese Drafter, National Health Commission The author and team leader of gastric cancer/colorectal cancer diagnosis and treatment specifications serve as the secretary-general of the Chinese Anti-Cancer Association Gastric Cancer Professional Committee Chairman of the MDT Specialty Committee of the Chinese Medical Doctor Association Surgeons Branch Chairman of the Chinese Anti-Cancer Association Oncology Drug Clinical Research Professional Committee of the Ministry of Science and Technology The chief expert of the key research and development program "Research on New Technologies for Targeted Treatment of Gastric Cancer" has undertaken nearly 10 national or provincial and ministerial-level projects, more than 30 international cooperation and horizontal projects, and published more than 120 SCI papers.
Won the second prize of National Science and Technology Progress Award, education The first prize of the Ministry of Science and Technology Progress, the first/second prize of the China Medical Science and Technology Award and other awards were honored as the national outstanding scientific and technological workers in 2016: [1] Rosemary J Akhurst.
Cold spring harb perspect Biol.
Targeting TGF-β Signaling for Therapeutic Gain.
2017;9(10):a022301.
[2] Huynh LK, Hipolito CJ, Ten Dijke P.
A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment.
Biomolecules.
2019 Nov 17;9(11) :743.
doi: 10.
3390/biom9110743.
[3] Sanjeev Mariathasan ,et al.
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
Nature.
2018;554(7693):544-548.
[4 ] Taku Okazaki,et al.
A rheostat for immune responses:the unique properties of PD-1 and their advantages for clinical application.
Nat Immunol.
2013;14(12):1212-8.
[5] Byung-Gyu Kim,et al.
Novel therapies emerging in oncology to target the TGF-β pathwayJ Hematol Oncol.
2021 Apr 6;14(1):55.