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Lupus nephritis (LN) is an autoimmune disease associated with genetic, hormonal, environmental, infection, drug and other factors
.
At present, no biomarkers with predictive value for the development of LN disease have been found for the time being, and more direct assessment of renal function is used to understand the damage to the kidneys caused by lupus erythematosus (SLE)
.
On March 25, 2022, Professor Chaim Putterman from the Albert Einstein College of Medicine in the United States accepted an interview with reporters and believed that T cells and activated leukocyte adhesion molecule (ALCAM) are the "center" of lupus nephritis and will open the LN A new world of management
.
Findings 1 Background CD6 is a co-stimulatory receptor found on activated CD4 and CD8 T cells, a ligand known as ALCAM on antigen presenting cells and on inflammatory tissues such as skin, gastrointestinal tract, kidney, etc.
express
.
2 Clinical studies Although LN is a common complication of SLE, not all patients with SLE will develop LN
.
Therefore, it is necessary to understand how patients with SLE and patients with LN differ
.
Professor Putterman and his research team examined 1038 patients with SLE and LN involving multiple ethnicities
.
The study found that creatinine-normalized urinary ALCAM levels were significantly elevated in patients with active LN compared with SLE patients or inactive LN
.
In contrast, creatinine-normalized urinary ALCAM levels in SLE patients were significantly higher than those in healthy controls
.
In addition, urinary ALCAM levels were significantly correlated with urinary TNF-α and IFN-γ levels
.
In renal tissue of LN patients, the expression of ALCAM, especially CD6, is elevated, and the level of urinary ALCAM is correlated with the disease state
.
An analysis of renal biopsies from 24 LN patients and 9 healthy controls showed that compared with healthy controls, more leukocytes and epithelial cells expressed CD6 and ALCAM in the kidneys of LN patients; In healthy people, the expression levels of CD6 and ALCAM positive cells were not different
.
It was suggested that the increase of CD6 and ALCAM was mainly related to the increase of the number of expressing cells, rather than the expression level of the average cells
.
In addition, the researchers found that the expression levels of ALCAM in the urine leukocytes of patients with LN were slightly higher than those in the kidney tissue, but because leukocytes are not normally present in the urine, they could not be compared with healthy controls
.
3 Animal models Since mice also have CD6 and ALCAM, researchers are prepared to use mouse models to validate the phenomena found in clinical studies
.
That is, if the expression of CD6 and ALCAM is changed, whether the mice develop SLE or LN
.
As expected, the mice developed SLE or LN, and blocking CD6 significantly improved the mice's health, including markers of immune inflammation and disease
.
The drug that blocks CD6 is Itolizumab, a human immunoglobulin monoclonal antibody that is associated with a variety of immune diseases and inflammation
.
In conclusion, Prof.
Putterman and his research team believe that ALCAM/CD6 is a novel biomarker for LN and even SLE patients, and blocking CD6 will help SLE and LN patients¹⁻²
.
Discussion and Interviews The reporter interviewed Professor Putterman and learned more details about the research from him
.
Reporter: How did your team get interested in CD6/ALCAM and its pathway? Prof.
Putterman: That's the interesting part, when Dr.
Chandra Mohan from the University of Houston was doing a biomarker study, he independently found high concentrations of CD6 in the urine of SLE patients
.
After observing the difference in urine between SLE, LN and healthy people, he found that CD6/ALCAM is the biggest difference between SLE, LN and healthy people
.
And this inspired me, if CD6 or ALCAM is lowered, can it help patients with SLE or LN? Reporter: Your findings seem to address the deficiencies in existing LN or SLE management, especially with regard to biomarkers
.
Prof.
Putterman: When we talk about inadequate management of patients with SLE or LN, physicians always want to find better and safer treatments
.
Clinically, many patients progress to end-stage renal disease (ESRD) despite treatment
.
Personally, this is a treatment failure
.
There are many possibilities that lead to ESRD, ranging from patient compliance issues to errors in the choice of treatment strategies
.
Many patients do not respond, or only partially respond, to first-line therapy
.
In the treatment of LN, physicians believe that "time is the kidney"
.
As nephritis continues, even if the patient eventually responds, some tissue damage that has already occurred is irreversible and can lead to further deterioration of renal function
.
Therefore, we need to develop new treatments that are both effective and faster
.
Reporter: It is reported that itolizumab has recently launched a phase 1 clinical trial.
What do you think is the focus of this trial? What was the most meaningful discovery? Prof.
Putterman: Itolizumab is being evaluated in patients with SLE and LN and has completed the first part, an open-label dose-escalation study
.
The study subjects were patients with active or inactive SLE, but not patients with active LN
.
Thirty-five patients received 5 different doses of subcutaneous injections, 0.
4 to 3.
2 mg/kg each, 14 days apart
.
The primary objective was to assess safety and tolerability, and secondary objectives were to assess pharmacokinetics and pharmacodynamics
.
The key finding was that itolizumab was well tolerated at 2.
4 mg/kg
.
And the expression of CD6 in CD4 cells was significantly decreased in a dose-dependent manner
.
Exploratory analysis showed decreased proteinuria and albuminuria in patients
.
These data will continue to support studies of Itolizumab in SLE, LN and other areas of rheumatic immunity
.
Reporter: In the history of human drug research, there are many cases where some drugs performed well in Phase 1 or Phase 2, but did not enter the market in the end.
Do you predict the future of Itolizumab? Prof.
Putterman: Through research, we have found that CD6/ALCAM is special in SLE and LN patients
.
If physicians can accurately identify patients who respond to specific interventions, the success rate of treatment can be improved
.
Therefore, when researching related drugs, we should try our best to know the change pattern of urinary CD6 and ALCAM levels and their correlation with disease onset
.
Future studies will look at the association of biomarkers with clinical manifestations
.
For example, the current first-line drug is mycophenolate mofetil, the second-line is cyclophosphamide, and the third-line is rituximab
.
But when does it change from the first line to the second line, or even the second line to the third line? The current practice can only track kidney indicators.
If the indicators do not improve after several months of treatment, other drugs are used.
However, at this time, the kidneys have been damaged or irreversible
.
And CD6 and ALCAM may be related to the patient's response to the therapeutic effect, or earlier than the change of renal function, so the treatment method can be replaced in a more timely manner, which is beneficial to the prognosis of the patient
.
Of course, because of Itolizumab's unique mechanism, Itolizumab and its analogs will hopefully be complementary to other therapies²
.
References: 1.
Chalmers SA, Ayilam Ramachandran R, Garcia SJ, et al.
The CD6/ALCAM pathway promoteslupus nephritis via T cell-mediated responses.
J Clin Invest.
2022 Jan 4;132(1):e147334.
2.
RobVolansky.
Q&A: CD6/ALCAM may hold key to more specific, effective therapies in lupus nephritis.
Healio.
Mar 25, 2022.
.
At present, no biomarkers with predictive value for the development of LN disease have been found for the time being, and more direct assessment of renal function is used to understand the damage to the kidneys caused by lupus erythematosus (SLE)
.
On March 25, 2022, Professor Chaim Putterman from the Albert Einstein College of Medicine in the United States accepted an interview with reporters and believed that T cells and activated leukocyte adhesion molecule (ALCAM) are the "center" of lupus nephritis and will open the LN A new world of management
.
Findings 1 Background CD6 is a co-stimulatory receptor found on activated CD4 and CD8 T cells, a ligand known as ALCAM on antigen presenting cells and on inflammatory tissues such as skin, gastrointestinal tract, kidney, etc.
express
.
2 Clinical studies Although LN is a common complication of SLE, not all patients with SLE will develop LN
.
Therefore, it is necessary to understand how patients with SLE and patients with LN differ
.
Professor Putterman and his research team examined 1038 patients with SLE and LN involving multiple ethnicities
.
The study found that creatinine-normalized urinary ALCAM levels were significantly elevated in patients with active LN compared with SLE patients or inactive LN
.
In contrast, creatinine-normalized urinary ALCAM levels in SLE patients were significantly higher than those in healthy controls
.
In addition, urinary ALCAM levels were significantly correlated with urinary TNF-α and IFN-γ levels
.
In renal tissue of LN patients, the expression of ALCAM, especially CD6, is elevated, and the level of urinary ALCAM is correlated with the disease state
.
An analysis of renal biopsies from 24 LN patients and 9 healthy controls showed that compared with healthy controls, more leukocytes and epithelial cells expressed CD6 and ALCAM in the kidneys of LN patients; In healthy people, the expression levels of CD6 and ALCAM positive cells were not different
.
It was suggested that the increase of CD6 and ALCAM was mainly related to the increase of the number of expressing cells, rather than the expression level of the average cells
.
In addition, the researchers found that the expression levels of ALCAM in the urine leukocytes of patients with LN were slightly higher than those in the kidney tissue, but because leukocytes are not normally present in the urine, they could not be compared with healthy controls
.
3 Animal models Since mice also have CD6 and ALCAM, researchers are prepared to use mouse models to validate the phenomena found in clinical studies
.
That is, if the expression of CD6 and ALCAM is changed, whether the mice develop SLE or LN
.
As expected, the mice developed SLE or LN, and blocking CD6 significantly improved the mice's health, including markers of immune inflammation and disease
.
The drug that blocks CD6 is Itolizumab, a human immunoglobulin monoclonal antibody that is associated with a variety of immune diseases and inflammation
.
In conclusion, Prof.
Putterman and his research team believe that ALCAM/CD6 is a novel biomarker for LN and even SLE patients, and blocking CD6 will help SLE and LN patients¹⁻²
.
Discussion and Interviews The reporter interviewed Professor Putterman and learned more details about the research from him
.
Reporter: How did your team get interested in CD6/ALCAM and its pathway? Prof.
Putterman: That's the interesting part, when Dr.
Chandra Mohan from the University of Houston was doing a biomarker study, he independently found high concentrations of CD6 in the urine of SLE patients
.
After observing the difference in urine between SLE, LN and healthy people, he found that CD6/ALCAM is the biggest difference between SLE, LN and healthy people
.
And this inspired me, if CD6 or ALCAM is lowered, can it help patients with SLE or LN? Reporter: Your findings seem to address the deficiencies in existing LN or SLE management, especially with regard to biomarkers
.
Prof.
Putterman: When we talk about inadequate management of patients with SLE or LN, physicians always want to find better and safer treatments
.
Clinically, many patients progress to end-stage renal disease (ESRD) despite treatment
.
Personally, this is a treatment failure
.
There are many possibilities that lead to ESRD, ranging from patient compliance issues to errors in the choice of treatment strategies
.
Many patients do not respond, or only partially respond, to first-line therapy
.
In the treatment of LN, physicians believe that "time is the kidney"
.
As nephritis continues, even if the patient eventually responds, some tissue damage that has already occurred is irreversible and can lead to further deterioration of renal function
.
Therefore, we need to develop new treatments that are both effective and faster
.
Reporter: It is reported that itolizumab has recently launched a phase 1 clinical trial.
What do you think is the focus of this trial? What was the most meaningful discovery? Prof.
Putterman: Itolizumab is being evaluated in patients with SLE and LN and has completed the first part, an open-label dose-escalation study
.
The study subjects were patients with active or inactive SLE, but not patients with active LN
.
Thirty-five patients received 5 different doses of subcutaneous injections, 0.
4 to 3.
2 mg/kg each, 14 days apart
.
The primary objective was to assess safety and tolerability, and secondary objectives were to assess pharmacokinetics and pharmacodynamics
.
The key finding was that itolizumab was well tolerated at 2.
4 mg/kg
.
And the expression of CD6 in CD4 cells was significantly decreased in a dose-dependent manner
.
Exploratory analysis showed decreased proteinuria and albuminuria in patients
.
These data will continue to support studies of Itolizumab in SLE, LN and other areas of rheumatic immunity
.
Reporter: In the history of human drug research, there are many cases where some drugs performed well in Phase 1 or Phase 2, but did not enter the market in the end.
Do you predict the future of Itolizumab? Prof.
Putterman: Through research, we have found that CD6/ALCAM is special in SLE and LN patients
.
If physicians can accurately identify patients who respond to specific interventions, the success rate of treatment can be improved
.
Therefore, when researching related drugs, we should try our best to know the change pattern of urinary CD6 and ALCAM levels and their correlation with disease onset
.
Future studies will look at the association of biomarkers with clinical manifestations
.
For example, the current first-line drug is mycophenolate mofetil, the second-line is cyclophosphamide, and the third-line is rituximab
.
But when does it change from the first line to the second line, or even the second line to the third line? The current practice can only track kidney indicators.
If the indicators do not improve after several months of treatment, other drugs are used.
However, at this time, the kidneys have been damaged or irreversible
.
And CD6 and ALCAM may be related to the patient's response to the therapeutic effect, or earlier than the change of renal function, so the treatment method can be replaced in a more timely manner, which is beneficial to the prognosis of the patient
.
Of course, because of Itolizumab's unique mechanism, Itolizumab and its analogs will hopefully be complementary to other therapies²
.
References: 1.
Chalmers SA, Ayilam Ramachandran R, Garcia SJ, et al.
The CD6/ALCAM pathway promoteslupus nephritis via T cell-mediated responses.
J Clin Invest.
2022 Jan 4;132(1):e147334.
2.
RobVolansky.
Q&A: CD6/ALCAM may hold key to more specific, effective therapies in lupus nephritis.
Healio.
Mar 25, 2022.
