-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
- Cosmetic Ingredient
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
For medical professionals only to read and refer to
the pioneer of integrin research recognized by the "Nobel Prize Wind Vane", let's see how GSALT biologics accurately treat IBD
.
The Lasker Awards, known as the "Nobel Prize weather vane", were officially announced on September 28
, US time 。 This year's Basic Medical Research Prize goes to three scholars who have made groundbreaking discoveries in integrin research – Dr.
Richard O.
Hynes of MIT, Dr.
Erkki Ruoslahti of the Sanford Burnham Prebys Institute, and Dr.
Timothy A.
Springer of Harvard Medical School/Boston Children's Hospital.
Research targeting integrins has led to breakthrough explorations
in the field of inflammatory bowel disease (IBD).
This article will reveal exactly what integrins are and how they are used in IBD precision therapy.
Richard O.
Hynes and Dr.
Erkki Ruoslahti independently discovered a cell surface-associated protein that helps cells adhere to the extracellular matrix (ECM).
Immediately after, the researchers captured a receptor that binds to this protein [1].
Dr.
Hynes used the term "integrin" to describe these complex molecules
that can "integrate" the ECM with the intracellular environment.
Integrins are transmembrane glycoprotein dimers consisting of a α subunit and a β subunit that bind to ligands in the extracellular matrix, molecules on other cell surfaces, and soluble proteins to mediate cell adhesion, migration, and proliferation[1].
Dr.
Timothy A.
Springer's contribution was the discovery of immune cell integrins and elucidating the dramatic changes
in their conformation when activated.
At the site of infection or inflammation, immune cell integrin is activated and mediates immune cell adhesion and extravasation into the infected tissue
.
Because integrin-mediated events involve tumor formation, metastasis, and autoimmune diseases, they are drug candidates of concern [1].
Despite significant efforts, integrin-targeting cancer drugs have not shown efficacy in therapeutic trials [1].
However, breakthroughs
have been made in the development of drugs for the treatment of inflammatory bowel disease (IBD).
IBD is essentially an inflammatory disease of the intestines caused by immune abnormalities [2].
The research on integrins has provided new ideas
for the research and development of therapeutic drugs.
Activated lymphocytes can cross the blood vessel wall, migrate outward to the intestinal mucosa, and enter the intestinal tissue [4], releasing a variety of inflammatory factors that induce and aggravate the inflammatory response, thereby causing inflammatory destruction of intestinal tissue (Fig.
1).
Fig.
1 Lymphocytes migrate to intestinal
lymphocytes through capillaries and determine their tissue-specific migration destinations
by expressing different types of integrins.
Among them, the main control of lymphocyte migration to the intestine is α4β7 integrin [5].
α4β7 integrin is present in more than 90% of intestinal mucosal T lymphocytes, and T lymphocytes bind to MAdCAM-1 expressed by venous vascular endothelial cells of intestinal tissue through α4β7 integrin, and can achieve selective migration to the gastrointestinal tract[6]
.
In addition, α4β7 integrin is only found in the B and T lymphocyte subsets of intestinal homing, accounting for 1%~3% of systemic lymphocytes, and does not affect the normal systemic immune response
.
The role of α4β7 integrin in the pathogenesis of IBD provides a new idea for the development of therapeutic drugs: by designing drugs specifically targeting α4β7 integrin, it can effectively inhibit the intestinal inflammatory response induced by lymphocytes without affecting systemic immune function, thereby theoretically improving the efficacy and reducing the risk
of systemic infection and cancer.
Therefore, intestinal selective anti-lymphocyte migration (GSALT) drugs represented by vedelizumab came into being
.
A large prospective real-world study found that normal doses of vedelizumab almost completely blocked the α4β7 receptor target in T lymphocytes in peripheral blood and intestinal tissue, indicating that the drug was effective in blocking the migration of T lymphocytes from the circulatory system to the intestine [7].
Fig.
2 Schematic diagram
of the mechanism of action of vedelizumab In addition, vedelizumab does not bind to any other α4 or β7 heterodimer, including α4β1 or αEβ7 integrins with different functions, making its therapeutic effect on IBD intestinally selective, and accurately targeting the inflammatory response of the intestine from the mechanism level.
It basically does not affect the normal immune function of other tissues in the human body, and is an anti-integrin biological agent
with both efficacy and safety.
The VERSIFY study, a phase 3b, multicenter, open-label, single-arm clinical trial of vedelizumab in patients with CD, showed that Patients with CD achieved endoscopic remission at weeks 26 and 52 of 11.
9 percent and 17.
9 percent, respectively, and had better outcomes in CD patients who had not previously received antitumor necrosis factor-α (TNF-α), with complete mucosal healing (visible disappearance of ulcers) of 19.
6 percent and 25 percent at weeks 26 and 52, respectively, confirming the efficacy of vedelizumab in patients with CD [8].
A newly released real-world study in China also verified the efficacy and safety of vedelizumab in the treatment of IBD patients in China [9].
The results showed that after 22 weeks of treatment, the clinical response rate of CD patients was 71.
4% and the clinical response rate was 87.
2%, and the endoscopic response rate was 29.
4% and 76.
5% by comparing the simplified endoscopic score of Crohn's disease (SES-CD) in 17 patients.
The clinical response rate of UC patients was 53.
9%, the clinical response rate was 76.
9%, and the endoscopic response rate and endoscopic response rate were both 57.
1%.
Of the 56 patients with IBD, only 1 developed an allergic rash, which resolved
with antiallergic therapy.
The results show that the short-term application of vedelizumab can effectively induce and maintain disease remission in patients with IBD, promote mucosal healing, and have a low adverse reaction rate and high
safety.
With the continuous enrichment of evidence-based evidence, vedelizumab has been recommended as a first-line biologic for IBD treatment by major guidelines at home and abroad [10,11].
The 2021 edition of the Expert Recommendations on Biologics for the Treatment of Inflammatory Bowel Disease states that vedelizumab is indicated for patients with moderately to severely active adult CD and UC who do not respond adequately, lose response, or tolerate to conventional treatments or anti-TNF-α monoclonal antibodies [11].
This article is for the sole purpose of providing scientific information to medical professionals and does not represent the position of
the platform.
the pioneer of integrin research recognized by the "Nobel Prize Wind Vane", let's see how GSALT biologics accurately treat IBD
.
The Lasker Awards, known as the "Nobel Prize weather vane", were officially announced on September 28
, US time 。 This year's Basic Medical Research Prize goes to three scholars who have made groundbreaking discoveries in integrin research – Dr.
Richard O.
Hynes of MIT, Dr.
Erkki Ruoslahti of the Sanford Burnham Prebys Institute, and Dr.
Timothy A.
Springer of Harvard Medical School/Boston Children's Hospital.
Research targeting integrins has led to breakthrough explorations
in the field of inflammatory bowel disease (IBD).
This article will reveal exactly what integrins are and how they are used in IBD precision therapy.
integrin research,
Bring new ideas for the treatment of a variety of diseases
In the early '70s, Dr.
Richard O.
Hynes and Dr.
Erkki Ruoslahti independently discovered a cell surface-associated protein that helps cells adhere to the extracellular matrix (ECM).
Immediately after, the researchers captured a receptor that binds to this protein [1].
Dr.
Hynes used the term "integrin" to describe these complex molecules
that can "integrate" the ECM with the intracellular environment.
Integrins are transmembrane glycoprotein dimers consisting of a α subunit and a β subunit that bind to ligands in the extracellular matrix, molecules on other cell surfaces, and soluble proteins to mediate cell adhesion, migration, and proliferation[1].
Dr.
Timothy A.
Springer's contribution was the discovery of immune cell integrins and elucidating the dramatic changes
in their conformation when activated.
At the site of infection or inflammation, immune cell integrin is activated and mediates immune cell adhesion and extravasation into the infected tissue
.
Because integrin-mediated events involve tumor formation, metastasis, and autoimmune diseases, they are drug candidates of concern [1].
Despite significant efforts, integrin-targeting cancer drugs have not shown efficacy in therapeutic trials [1].
However, breakthroughs
have been made in the development of drugs for the treatment of inflammatory bowel disease (IBD).
IBD is essentially an inflammatory disease of the intestines caused by immune abnormalities [2].
The research on integrins has provided new ideas
for the research and development of therapeutic drugs.
α4β7 integrin,
An important target for precision therapy of IBD
Since the 90s of last century, a large number of basic scientific research has gradually revealed the pathogenesis of IBD from the molecular level, and found that the increased migration of T cells to the intestine is the key to the abnormal immune response of IBD patients [3].
Activated lymphocytes can cross the blood vessel wall, migrate outward to the intestinal mucosa, and enter the intestinal tissue [4], releasing a variety of inflammatory factors that induce and aggravate the inflammatory response, thereby causing inflammatory destruction of intestinal tissue (Fig.
1).
Fig.
1 Lymphocytes migrate to intestinal
lymphocytes through capillaries and determine their tissue-specific migration destinations
by expressing different types of integrins.
Among them, the main control of lymphocyte migration to the intestine is α4β7 integrin [5].
α4β7 integrin is present in more than 90% of intestinal mucosal T lymphocytes, and T lymphocytes bind to MAdCAM-1 expressed by venous vascular endothelial cells of intestinal tissue through α4β7 integrin, and can achieve selective migration to the gastrointestinal tract[6]
.
In addition, α4β7 integrin is only found in the B and T lymphocyte subsets of intestinal homing, accounting for 1%~3% of systemic lymphocytes, and does not affect the normal systemic immune response
.
The role of α4β7 integrin in the pathogenesis of IBD provides a new idea for the development of therapeutic drugs: by designing drugs specifically targeting α4β7 integrin, it can effectively inhibit the intestinal inflammatory response induced by lymphocytes without affecting systemic immune function, thereby theoretically improving the efficacy and reducing the risk
of systemic infection and cancer.
Therefore, intestinal selective anti-lymphocyte migration (GSALT) drugs represented by vedelizumab came into being
.
From mechanism to clinic,
GSALT biologics have both efficacy and safety
As a humanized monoclonal antibody, vedelizumab binds to α4β7 integrin on the surface of T cells and inhibits its activation, thereby preventing lymphocyte adhesion, fixation, and migration to the intestine (Figure 2).
A large prospective real-world study found that normal doses of vedelizumab almost completely blocked the α4β7 receptor target in T lymphocytes in peripheral blood and intestinal tissue, indicating that the drug was effective in blocking the migration of T lymphocytes from the circulatory system to the intestine [7].
Fig.
2 Schematic diagram
of the mechanism of action of vedelizumab In addition, vedelizumab does not bind to any other α4 or β7 heterodimer, including α4β1 or αEβ7 integrins with different functions, making its therapeutic effect on IBD intestinally selective, and accurately targeting the inflammatory response of the intestine from the mechanism level.
It basically does not affect the normal immune function of other tissues in the human body, and is an anti-integrin biological agent
with both efficacy and safety.
The VERSIFY study, a phase 3b, multicenter, open-label, single-arm clinical trial of vedelizumab in patients with CD, showed that Patients with CD achieved endoscopic remission at weeks 26 and 52 of 11.
9 percent and 17.
9 percent, respectively, and had better outcomes in CD patients who had not previously received antitumor necrosis factor-α (TNF-α), with complete mucosal healing (visible disappearance of ulcers) of 19.
6 percent and 25 percent at weeks 26 and 52, respectively, confirming the efficacy of vedelizumab in patients with CD [8].
A newly released real-world study in China also verified the efficacy and safety of vedelizumab in the treatment of IBD patients in China [9].
The results showed that after 22 weeks of treatment, the clinical response rate of CD patients was 71.
4% and the clinical response rate was 87.
2%, and the endoscopic response rate was 29.
4% and 76.
5% by comparing the simplified endoscopic score of Crohn's disease (SES-CD) in 17 patients.
The clinical response rate of UC patients was 53.
9%, the clinical response rate was 76.
9%, and the endoscopic response rate and endoscopic response rate were both 57.
1%.
Of the 56 patients with IBD, only 1 developed an allergic rash, which resolved
with antiallergic therapy.
The results show that the short-term application of vedelizumab can effectively induce and maintain disease remission in patients with IBD, promote mucosal healing, and have a low adverse reaction rate and high
safety.
With the continuous enrichment of evidence-based evidence, vedelizumab has been recommended as a first-line biologic for IBD treatment by major guidelines at home and abroad [10,11].
The 2021 edition of the Expert Recommendations on Biologics for the Treatment of Inflammatory Bowel Disease states that vedelizumab is indicated for patients with moderately to severely active adult CD and UC who do not respond adequately, lose response, or tolerate to conventional treatments or anti-TNF-α monoclonal antibodies [11].
small
knot
This year's Lasker Prize focuses on integrins that have dramatically changed the perception of cell-cell interactions and are one of
the key discoveries in biology over the past 40 years.
In the field of IBD, the continuous research on related integrins has also brought new breakthroughs
in the development of therapeutic drugs.
GSALT drug vedelizumab only binds to integrin α4β7, which can accurately inhibit intestinal inflammation without affecting systemic immune function, and takes into account both efficacy and safety in the treatment of IBD, so it is recommended by major guidelines at home and abroad as a first-line biological agent for IBD treatment, and it is expected to bring more benefits
to IBD patients.
References:
[1] Fagerholm SC.
N Engl J Med.
2022 Sep 28.
[2] Guan Q.
J Immunol Res.
2019 Dec 1; 2019:7247238.
[3] Panés J,et al.
J Crohns Colitis.
2018 Aug 22; 12(suppl_2):S633-S640.
[4] Lobatón T,et al.
Aliment Pharmacol Ther.
2014 Mar; 39(6):579-594.
[5] Coskun M,et al.
Trends Pharmacol Sci.
2017 Feb; 38(2):127-142.
[6] Ley K,et al.
Nat Rev Drug Discov.
2016 Mar; 15(3):173-183.
[7] Ungar B,et al.
Clin Gastroenterol Hepatol.
2018 May; 16(5):697-705.
e7.
[8] Gastroenterology.
2019 Jul 4.
pii:S0016-5085(19)41080-9.
[9] Yao Jiayin, et al.
Journal of Clinical and Pathology,2022,42(8):1841-1846.
[10] Raine T,et al.
J Crohns Colitis.
2022 Jan 28; 16(1):2-17.
[11] China Center for Quality Control and Evaluation of Diagnosis and Treatment of Inflammatory Bowel Disease, et al.
Chinese Journal of Inflammatory Bowel Disease,2021,05(03):193-206.
Approval number: VV-MEDMAT-76600
Date of approval: October 2022
Disclaimer: This information is intended to help healthcare professionals better understand the latest developments
in related disease areas.
This platform does not agree with its description and views on the content of the information released, but only provides more information
.
If copyright issues are involved, please contact us and we will deal with it
as soon as possible.
The information provided in this information is not in any way a substitute for professional medical advice and should not be construed as medical advice
.
If such information is used for purposes other than information, this platform, the author and Takeda shall not be liable
in connection with it.
This article is for the sole purpose of providing scientific information to medical professionals and does not represent the position of
the platform.
