PD-(L)1 Dual Anti-Partner Heat Competition: TGFβ Throne Steady and 4-1BB Strongly Rise

On the 14th, the Insight database showed that Hisun Pharmaceutical’s PD-L1/TGFβ bifunctional fusion protein BR102 was launched for the first time in clinical practice

From: Insight database (http://db.

In the frenzy of PD-1/L1, domestic companies have turned their R&D direction to new targets and new technologies, including other immune checkpoints such as TIGIT, CTLA-4, LAG-3, or double antibodies, ADCs, and cells.

Among those PD-1/L1 partners, who is the hottest at home and abroad? Insight compiled the domestic and foreign target hot competition, and the top 4 were them: TGFβ, 4-1BB, CD47, CTLA-4

*Manually organize, welcome to add any omissions

TGFβ: The absolute king, most of the R&D projects come from China

Whether it is global or domestic, the most popular target partner is TGFβ

From the time of the first clinical application, Hengrui was the first company to declare and the fastest progressing company, taking the lead in entering Phase II/III clinical trials

Before 2021, including Merck, only these four domestic products have entered the clinical stage, but in 2021 ushered in the peak of the declaration of PD-(L)1/TGFβ dual-target drugs.

Domestic PD-(L)1/TGFβ dual target drug application and progress

From: Insight database (http://db.

The enthusiasm for PD-(L)1/TGFβ development is largely derived from Merck's M7824

The results showed that among the 40 patients in the 1200 mg dose group, M7824 was the second-line treatment of advanced NSCLC, the total population ORR was 27.

From: Merck

The three-year follow-up results of the study were announced at the ESMO conference in 2020.

However, the follow-up development of this star drug does not seem to be very positive.

The first clinical failure of M7824 came from the Phase 3 clinical trial of head-to-head PK with K drug

On March 16, German Merck announced another clinical failure of M7824, failing to reach the preset primary endpoint

However, there are many reasons for the failure of clinical research.

4-1BB: A new star target

Although the domestic 4-1BB ranks fourth, the global 4-1BB fever is close to TGFβ.

4-1BB, or CD137, is a member of the tumor necrosis factor receptor superfamily (TNFRSF9), which is mainly expressed in activated T cells, NK cells and dendritic cells and other tumor immune cells
.
Studies have shown that anti-4-1BB agonistic antibodies can induce CD8+ T cells to release more effector molecules, increase proliferation, and reduce CD8+ T cell apoptosis, thereby enhancing anti-tumor immunity
.

In the development of 4-1BB targeting antibodies, hepatotoxicity is the main problem it faces, and the double antibody is expected to enhance its pharmacological effects while reducing hepatotoxicity
.
At present, the research and development of double antibodies for 4-1BB is at an early stage, and the fastest in the world is only to clinical phase I/II, which are Kewang Bio/Inhibrx's ES101 and Genmab/BioNTech's GEN1046
.

PD-(L)1/4-1BB Global New Drug Project

Finished by Insight, as of 2021.
9.
14

Kewang’s ES101 (INBRX-105) was introduced from Inhibrx, and Kewang has its rights in Greater China
.
This is a tetravalent bispecific antibody targeting PD-L1 and 4-1BB, with a PD-L1 binding-dependent activation mechanism of 4-1BB
.
ES101 realizes the concept of "refueling" for immune cell activation
.
De-gate is the release of PD-1/PD-L1 pathway inhibition by PD-L1 antibody; refueling is the activation of immune cells mediated by 4-1BB by 4-1BB antibody
.

According to the Insight database, ES101 started clinical trials for the first time in May 2019, and phase 1b/2 clinical trials were launched in April 2021
.

From: Insight database (http://db.
dxy.
cn/v5/home/)

Genmab/BioNTech’s GEN1046 also announced Phase 1/2a clinical data at 2021SITC.
The study included 61 patients with advanced solid tumors, 37% of which had previously received PD-1/-L1
.
The results showed that the ORR of GEN1046 treatment was 6.
5% (4/61), and the DCR reached 65.
6%.
Part of it was observed in 1 case of triple-negative breast cancer, 1 case of ovarian cancer and 2 cases of non-small cell lung cancer (2/6).
Ease
.

In addition to TGFβ and 4-1BB, CD47, CTLA-4, TIM-3, and LAG-3 are also popular in the development of double antibodies, whether it is the research of monoclonal antibody combination drugs or the development of double antibodies
.

However, it is worth mentioning that, in addition to TGFβ and classic CTLA-4 entering Phase 3, most of the double-antibody products are still in early clinical development
.

Note: The original text has been deleted