Gold-absorbing target next one-CD137 to see how pharmaceutical giants set off an upsurge in research and development

CD137, also known as 4-1BB, is an important member of the tumor necrosis factor (TNF) receptor family
.
It is a T cell costimulatory immune checkpoint molecule, which is mainly expressed on activated T cells and on many non-T cells such as natural killer cells (NK cells), dendritic cells (DC cells), and macrophages.

Contrary to PD-1/PD-L1's "brake" effect, 4-1BB can induce activation of these cells by binding to its ligand, thereby enhancing their killing ability to cancer cells
.

Status of foreign R&D

In recent years of research and development, the 4-1BB antibody has shown great potential, so more and more companies are deploying in this field, including large pharmaceutical companies such as Bristol-Myers Squibb (BMS) and Pfizer (Pfizer)
.

BMS-Urelumab

BMS's Urelumab is a fully human IgG4 mAb and the first anti-4-1BB therapeutic drug to enter clinical trials
.
Urelumab does not block the interaction of 4-1BB with its ligand

Pfizer-Utomilumab

Pfizer's Utomilumab is a humanized IgG2 monoclonal antibody that activates 4-1BB while blocking the binding to endogenous 4-1BBL
.
In 2014, preliminary clinical data on the use of utomilumab were reported and revealed that utomilumab may have higher safety than urelumab

BioNTech——DuoBody-PD-L1x4-1BB

BioNTech’s DuoBody-PD-L1x4-1BB is a new bispecific antibody that combines the checkpoint blockade of the inhibitory PD-1/PD-L1 signal axis, which conditions T cells by activating the 4-1BB receptor Sexual stimulation, thereby enhancing the proliferation of activated T cells, allowing cells to effectively target cancer cells
.
Clinical trials are currently being conducted in patients with metastatic or unresectable malignant solid tumors

Aptevo——ALG.
APV-527

Aptevo's ALG.
APV-527 is an anti-4-1BB x anti-5T4 bispecific antibody drug used to treat a variety of 5T4-positive solid tumors
.
In preclinical studies, it has been shown that ALG.

Domestic R&D status

There are also some leading 4-1BB antibody companies in China, and there are more and more researches on 4-1BB drugs
.

Tianyan Pharmaceutical——ADG106

ADG106 is a fully human agonistic antibody developed by Tianyan Pharmaceutical that targets human, monkey and mouse 4-1BB conserved epitopes and can produce cross-reactions.
It activates in a natural ligand-like manner.
4 -1BB also blocks the negative feedback signal mediated by 4-1BB ligand and has a significant specific cross-linking reaction
.
Currently, ADG106 is undergoing clinical trials in the United States and China at the same time

       At the 2020 American Society of Clinical Oncology (ASCO) annual meeting, Tianyan Pharmaceuticals announced the results of a phase I clinical trial of ADG106 in patients with non-Hodgkin’s lymphoma and solid tumors in China
.
Studies have shown that ADG106 shows good safety characteristics and preliminary anti-tumor activity: after a patient with non-Hodgkin’s lymphoma who had failed multi-line therapy received ADG106, the tumor burden of two of the six target lesions was reduced More than 50%; in addition, in many patients, potential biological activity and pharmacodynamic biomarker responses were also observed, including related changes in the expression of 4-1BB

       Wuxi Zhikang Hongyi——WBP3425

       In 2019, Wuxi Zhikang Hongyi's clinical application of 4-1BB antibody WBP3425 was accepted by NMPA, becoming the second company in China to declare this target antibody
.
After that, it was approved for clinical trials at the end of 2019, and it is intended to be used for the treatment of solid tumors

       Huaiyue Bio-PE0116

       In 2020, the clinical trial application of Huaiyue Biologics 4-1BB antibody PE0116 was approved by NMPA
.
PE0116 is an Fc cross-lInking-dependent 4-1BB agonist antibody
.

       Kewang Bio-ES101

       Eager Bio's ES101 is a world-first, quadrivalent bispecific antibody that targets PD-L1 and 4-1BB at the same time.
The activation of T cells induced by 4-1BB depends on the combination of the drug and PD-L1 in the tumor microenvironment
.

       In February 2019, Inhibrx, the US partner of the ES101 project, announced the completion of the first patient in the United States and obtained the implied approval of the CDE clinical trial.
This means that the ES101 bispecific antibody will be clinically tested in China and the United States.
It is expected to benefit cancer patients worldwide
.

       CStone Pharmaceuticals-ND021 (NM21-1480)

       ND021 was jointly developed by CStone Pharmaceuticals and Numab Therapeutics AG of Switzerland.
It is a monovalent trispecific antibody fragment molecule targeting PD-L1, 4-1BB and human serum albumin (HSA)
.

       ND021 only binds to the unique epitope of 4-1BB when it binds to PD-L1 on the surface of tumor cells to activate anti-cancer T cells, which may avoid the appearance of traditional 4-1BB agonist monoclonal antibodies in human trials Hepatotoxicity observed in
.

       Compared with other PD-L1/4-1BB bispecific candidate antibodies, ND021's unique monovalent structure and ultra-high affinity for PD-L1 are expected to achieve better safety and better efficacy
.
In addition, the half-life of ND021 can be prolonged by combining HSA, thereby reducing the frequency of patient administration
.
ND021 is also expected to be effective against a broad spectrum of tumor types with PD-L1 expression, and may overcome the primary and secondary resistance to PD-1/PD-L1 antibodies
.
Therefore, ND021 is very likely to become a leading drug for the next generation of tumor immunotherapy and a new backbone drug molecule for tumor combination therapy
.

       Heavenly creature——TJ-CD4B

       TJ-CD4B is an innovative bispecific antibody that simultaneously targets the tumor antigen claudin 18 splice 2 (Claudin 18.
2) and 4-1BB.
Claudin 18.
2 is highly specifically expressed in multiple cancers, especially gastric cancer and pancreatic cancer
.
After TJ-CD4B specifically binds to these two targets, it can increase lymphocyte tumor infiltration and enhance tumor immune response
.

       Preclinical studies have shown that even in the case of low expression of Claudin 18.
2, TJ-CD4B can still bind to tumor cells and produce better immune activity than other 4-1BB monoclonal antibodies, making it expected to be suitable for a wider range of patients Groups
.
In addition, TJ-CD4B also has a unique 4-1BB binding epitope, which makes it activate T cells only when it binds to Claudin 18.
2
.
This feature avoids liver toxicity caused by excessive activation of T cells due to the widespread expression of 4-1BB and reduces the risk of systemic immune response
.

       A multi-center phase I dose-climbing trial has been carried out in the United States to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TJ-CD4B in patients with advanced or metastatic solid tumors
.

       Lijin Bio-LVGN6051

       LVGN6051 is an anti-4-1BB agonistic antibody developed by Eli Jin Biologics.
After administration, LVGN6051 binds and activates 4-1BB expressed on various white blood cell subsets, including activated T lymphocytes and natural killer (NK) cells
.
This enhances 4-1BB-mediated signal transduction, induces the production of cytokines, and promotes the anti-tumor immune response mediated by T cells
.
Unlike the first-generation 4-1BB agonistic antibody that has entered the clinic, LVGN6051 selectively activates 4-1BB locally in the tumor microenvironment, reducing normal tissue immune side effects
.

       Phase I clinical trials are currently underway in the United States
.
Prior to this, the product has reached a joint drug cooperation with Merck’s Keytruda to evaluate the efficacy of the combined drug in the treatment of multiple malignant tumors
.

       4-1BB is a promising therapeutic target.
Although there is no commercial product on the market, its clinical value has been initially verified
.
The new bispecific antibody not only has high selectivity, but also better avoids liver toxicity
.
It is an ideal supplement for PD-1/L1 immunotherapy
.

       With the discovery of the mechanism of action, combination with other tumor targets and specific activation of the tumor microenvironment have become important directions for exploration
.
The combination of drugs and the development of bispecific antibodies have given new vitality to 4-1BB.
As more and more pharmaceutical companies deploy in this field, 4-1BB has become a research and development hotspot
.
What the future holds, let us wait and see
.

       refer to:

       1.
Chinese cancer biotech Adagene files for a $125 million US IPO.
Retrieved Jan 19, 2021, from https:// million-us-ipo-2021-01-19.

       2.
Retrieved Mar 30 2021, from https://       3.
Retrieved Aug 12, 2020, from http://#.

       4.
Lyvgen Announces Clinical Trial Collaboration With MSD.
Retrieved June 9, 2020, from https://