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▎WuXi AppTec's content team editing cytokine IL-2 was approved by the US FDA nearly 30 years ago as an anti-cancer immunotherapy
.
Subsequent studies found that it also has an important role in regulating immune tolerance through regulatory T cells (Treg)
.
The elucidation of the crystal structure of IL-2 binding to its receptor provides important structural information for stimulating the development of cell-type-specific IL-2 candidate therapies
.
Today, a number of IL-2 biological products have entered the clinical development stage
.
Recently, a review in Nature Reviews Immunology took stock of four strategies for engineering IL-2 to treat cancer and autoimmune diseases
.
Signaling of IL-2 IL-2 is a multifunctional cytokine secreted mainly by CD4-positive T cells
.
It modulates immune responses by binding to the IL-2 receptor (IL-2R)
.
IL-2R is divided into two types, high-affinity IL-2R consists of three subunits, α chain (CD25), β chain (CD122) and γ chain (CD132)
.
High-affinity IL-2R is mainly expressed on the surface of Treg cells, newly activated CD4-positive and CD8-positive effector T cells, some natural killer (NK) cells and NKT cells
.
The intermediate-affinity IL-2R consists of two subunits (CD122 and CD132) and is mainly expressed on the surface of CD8-positive memory T cells and most NK cells
.
IL-2R signaling not only affects the proliferation of effector T cells, Treg cells, NK cells, etc.
, but also shapes their functional activity
.
▲ Lymphocyte types expressing high-affinity IL-2R (right) and medium-affinity IL-2R (left) (Image source: Reference [1]) Unmodified IL-2 has been approved to treat renal cell carcinoma and melanin cancer, but treating cancer with high doses of IL-2 faces multiple obstacles
.
The short half-life of native IL-2 (<15 minutes) results in the need for very high doses of IL-2 infused intravenously, which can cause severe nonspecific toxicity
.
Moreover, since IL-2 can also activate Treg, and Treg in the tumor microenvironment usually play an immunosuppressive role, it may counteract the anticancer immune response stimulated by IL-2
.
Therefore, the current research direction is to develop IL-2 analogs that only activate specific lymphocyte types through protein engineering of IL-2
.
Four strategies to engineer IL-2 The generation of IL-2 analogs that bind to specific lymphocyte types is inseparable from an understanding of the interaction of IL-2 and IL-2R subunits
.
The binding of IL-2 to high-affinity IL-2R can be divided into two steps: low-concentration IL-2 first binds to CD25 with high affinity to form a binary complex, which then binds to the complex composed of CD122 and CD132 to form a binary complex.
Generate stable quaternary complexes
.
High concentrations of IL-2 can directly combine with the complex composed of CD122 and CD132 to form a ternary complex
.
If the modification of IL-2 enhances its ability to bind to CD25, IL-2 will tend to bind to high-affinity receptors, and if it enhances the ability of IL-2 to bind to CD122, it will tend to bind to medium-affinity receptors.
receptor binding
.
The IL-2 analogs currently in clinical development include four strategies to engineer IL-2
.
IL-2 mutants IL-2 mutants alter specific amino acids on the surface of the IL-2 protein by introducing genetic mutations
.
Crystal structure studies of IL-2 and IL-2R complexes have resolved the amino acids that play a key role in the binding of IL-2 to different IL-2R subunits
.
By modifying these amino acids, IL-2 mutants that tend to bind to high- or medium-affinity receptors can be generated
.
An example of such a mutant is Amgen's efavaleukin alfa
.
This investigational therapy fuses IL-2 with a specific mutation to the Fc end of the antibody.
The resulting fusion protein not only has a longer half-life, but also tends to bind to high-affinity receptors
.
This allows it to promote the proliferation of Treg cells, thereby restoring the immune balance in patients with autoimmune diseases
.
It is currently in Phase 2b clinical trials for the treatment of patients with systemic lupus erythematosus (SLE) and ulcerative colitis
.
Image source: Preliminary results from Amgen.
com in SLE patients show that efavaleukin alfa selectively expands Treg cells in the bloodstream
.
Polyethylene glycol-modified IL-2 Coupling polyethylene glycol (PEG) on the surface of IL-2 protein can prolong the half-life of IL-2 protein
.
By controlling the position and quantity of polyethylene glycol coupling on the surface of IL-2, IL-2 analogs that tend to bind to high-affinity receptors or medium-affinity receptors can be constructed
.
For example, bempegaldesleukin (NKTR-214) developed by Nektar Therapeutics has an average of 6 PEG chains coupled near the interface where IL-2 binds to CD25
.
This PEG modification effectively blocked its binding to the high-affinity IL-2R receptor, making bempegaldesleukin more inclined to activate CD8-positive memory T cells and NK cells
.
Bristol-Myers Squibb and Nektar have entered into an R&D agreement to evaluate bempegaldesleukin in combination with the anti-PD-1 antibody Opdivo in multiple tumor types
.
There are currently 5 clinical trials with registration potential in progress, but Bristol-Myers Squibb recently announced that a Phase 3 clinical trial of this combination therapy in melanoma did not meet the primary endpoint
.
A defect of some PEG-modified IL-2 (such as bempegaldesleukin) is that the PEG-modified sites are not consistent between different protein molecules, which may cause some IL-2 proteins to fail to selectively activate CD8-positive T cells and NK cells, thereby affecting the efficacy of candidate therapies
.
To solve this problem, some biotech companies introduced unnatural amino acids on the surface of IL-2 and coupled PEG chains to these unnatural amino acids
.
This method can precisely locate the conjugation site of PEG on the surface of IL-2, possibly generating more homogenous IL-2 analogs
.
Sanofi's SAR444245 (formerly THOR707) is one such IL-2 analog
.
By introducing unnatural amino acids on the interface between IL-2 protein and CD25, it precisely connects PEG chains on the surface of IL-2, and blocks the binding of IL-2 and CD25
.
Sanofi said the IL-2 analog may have "best-in-class" potential
.
It is currently being tested in multiple Phase 2 clinical trials, in combination with PD-1 inhibitors or other anti-cancer therapies, in a number of different cancer types
.
▲Introduction to SAR444245 (Image source: Sanofi official website) IL-2 immune complex IL-2 combined with anti-IL-2 monoclonal antibody to form a complex also prolongs the half-life of IL-2 protein and regulates the receptor binding selection of IL-2 a way of sex
.
Monoclonal antibodies targeting IL-2 can block the binding of IL-2 to CD25 or CD122 by binding to specific epitopes of IL-2, thereby giving them selective binding to high-affinity IL-2R or medium-affinity IL-2R ability to combine
.
Anaveon's selective IL-2R agonist ANV419 follows this model
.
It fuses a monoclonal antibody targeting the binding site of IL-2 to CD25 to IL-2, thereby blocking the binding of IL-2 to CD25
.
This fusion protein still has the ability to bind to the medium-affinity IL-2R receptor, so it can selectively activate CD8-positive memory T cells and NK cells
.
Binding to the antibody also extends its half-life
.
▲A schematic diagram of the mechanism of action of ANV419 (Image source: Anaveon's official website) Anaveon completed a Series B financing of about US$120 million at the end of last year, and the investors included the venture capital department of Pfizer and Novartis
.
IL-2-CD25 fusion protein Another strategy to selectively bind IL-2 to the medium-affinity IL-2R receptor is to fuse IL-2 with soluble CD25, and the resulting fusion protein can no longer bind to cell surface CD25.
Binding, thereby blocking the binding to high-affinity IL-2R
.
One such fusion protein is nemvaleukin alfa (ALKS 4230) developed by Alkermes
.
It does not activate Treg cells while activating CD8-positive memory T cells and NK cells by selectively binding to the medium-affinity IL-2R receptor
.
▲The mechanism of action of Nemvaleukin alfa (Image source: Reference [7]) This investigational therapy has obtained two fast-track qualifications granted by the US FDA, which are used in combination with anti-PD-1 antibodies to treat platinum-containing chemotherapy resistance.
Ovarian cancer, and mucosal melanoma
.
Clinical development has entered into Phase 2 and Phase 3 clinical trials
.
The authors of a review of the pros and cons of different strategies for modifying IL-2 suggest that these different strategies for modifying IL-2 also have their own pros and cons
.
For example, IL-2 mutants can effectively confer selectivity to IL-2 protein binding to specific IL-2Rs by changing the amino acids on the surface of IL-2.
2 mutants are considered foreign proteins by the body's immune system, triggering an immune response against IL-2 mutants, thereby reducing the efficacy of potential therapies
.
PEGylation of IL-2, IL-2 immune complexes and IL-2-CD25 fusion proteins could theoretically confer selectivity to IL-2 without introducing mutations, thereby reducing the immunogenicity of candidate therapies
.
However, they also have their own shortcomings.
If the site of PEG modification is uncertain, it may lead to product heterogeneity and affect the overall therapeutic effect
.
The IL-2 immune complex may release free IL-2 in the blood circulation, leading to stimulation of other unwanted immune cells
.
Although we have a variety of strategies to engineer IL-2 to give them the ability to selectively activate anticancer immune responses or suppress overactive immune responses, which strategy is safer and more effective still needs follow-up clinical trials to verify
.
A variety of IL-2 analogs are currently in clinical development, and the review authors say that in the coming years we will see whether these advances in IL-2 engineering can lead to effective anti-cancer and innovative treatments for autoimmune diseases
.
Reference: [1] Hernandez et al.
, (2022).
Engineering IL-2 for immunotherapy of autoimmunity and cancer.
Nature Reviews Immunology, https://doi.
org/10.
1038/s41577-022-00680-w[2] Amgen Business Review.
Retrieved March 9, 2022, from https://investors.
amgen.
com/static-files/6d823d7d-2fd1-405a-8c0e-22aa91bee682[3] Nektar Therapeutics Corporate Presentation.
Retrieved March 9, 2022, from https ://ir.
nektar.
com/static-files/7818281a-1882-4952-9ebc-7680643f109a[4] Sanofi Oncology ASCO Event.
Retrieved March 9, 2022, from https:// /Project/One-Sanofi-Web/Websites/Global/Sanofi-COM/Home/common/docs/investors/2021_06_04_ASCO_Slides_FINAL.
pdf?la=en&hash=A961668213E13C37545571B90B46939B[5] Anaveon.
Retrieved March 9, 2022, from https:// anaveon.
com/our-approach/[6] Alkermes to Present Data on Nemvaleukin Alfa at the Society of Gynecologic Oncology 2022 Annual Meeting on Women's Cancer.
Retrieved March 9, 2022, from https:// alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/10.
1124/jpet.
121.
000612 Disclaimer Statement: WuXi AppTec content team focuses on introducing global biomedical health research progresscom/news-releases/alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/ 10.
1124/jpet.
121.
000612 Disclaimer: WuXi AppTec content team focuses on introducing global biomedical health research progresscom/news-releases/alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/ 10.
1124/jpet.
121.
000612 Disclaimer: WuXi AppTec content team focuses on introducing global biomedical health research progress
.
This article is for information exchange purposes only, and the views expressed in this article do not represent WuXi AppTec's position, nor do they represent WuXi AppTec's support or opposition to the views expressed in this article
.
This article is also not a treatment plan recommendation
.
For guidance on treatment options, please visit a regular hospital
.
.
Subsequent studies found that it also has an important role in regulating immune tolerance through regulatory T cells (Treg)
.
The elucidation of the crystal structure of IL-2 binding to its receptor provides important structural information for stimulating the development of cell-type-specific IL-2 candidate therapies
.
Today, a number of IL-2 biological products have entered the clinical development stage
.
Recently, a review in Nature Reviews Immunology took stock of four strategies for engineering IL-2 to treat cancer and autoimmune diseases
.
Signaling of IL-2 IL-2 is a multifunctional cytokine secreted mainly by CD4-positive T cells
.
It modulates immune responses by binding to the IL-2 receptor (IL-2R)
.
IL-2R is divided into two types, high-affinity IL-2R consists of three subunits, α chain (CD25), β chain (CD122) and γ chain (CD132)
.
High-affinity IL-2R is mainly expressed on the surface of Treg cells, newly activated CD4-positive and CD8-positive effector T cells, some natural killer (NK) cells and NKT cells
.
The intermediate-affinity IL-2R consists of two subunits (CD122 and CD132) and is mainly expressed on the surface of CD8-positive memory T cells and most NK cells
.
IL-2R signaling not only affects the proliferation of effector T cells, Treg cells, NK cells, etc.
, but also shapes their functional activity
.
▲ Lymphocyte types expressing high-affinity IL-2R (right) and medium-affinity IL-2R (left) (Image source: Reference [1]) Unmodified IL-2 has been approved to treat renal cell carcinoma and melanin cancer, but treating cancer with high doses of IL-2 faces multiple obstacles
.
The short half-life of native IL-2 (<15 minutes) results in the need for very high doses of IL-2 infused intravenously, which can cause severe nonspecific toxicity
.
Moreover, since IL-2 can also activate Treg, and Treg in the tumor microenvironment usually play an immunosuppressive role, it may counteract the anticancer immune response stimulated by IL-2
.
Therefore, the current research direction is to develop IL-2 analogs that only activate specific lymphocyte types through protein engineering of IL-2
.
Four strategies to engineer IL-2 The generation of IL-2 analogs that bind to specific lymphocyte types is inseparable from an understanding of the interaction of IL-2 and IL-2R subunits
.
The binding of IL-2 to high-affinity IL-2R can be divided into two steps: low-concentration IL-2 first binds to CD25 with high affinity to form a binary complex, which then binds to the complex composed of CD122 and CD132 to form a binary complex.
Generate stable quaternary complexes
.
High concentrations of IL-2 can directly combine with the complex composed of CD122 and CD132 to form a ternary complex
.
If the modification of IL-2 enhances its ability to bind to CD25, IL-2 will tend to bind to high-affinity receptors, and if it enhances the ability of IL-2 to bind to CD122, it will tend to bind to medium-affinity receptors.
receptor binding
.
The IL-2 analogs currently in clinical development include four strategies to engineer IL-2
.
IL-2 mutants IL-2 mutants alter specific amino acids on the surface of the IL-2 protein by introducing genetic mutations
.
Crystal structure studies of IL-2 and IL-2R complexes have resolved the amino acids that play a key role in the binding of IL-2 to different IL-2R subunits
.
By modifying these amino acids, IL-2 mutants that tend to bind to high- or medium-affinity receptors can be generated
.
An example of such a mutant is Amgen's efavaleukin alfa
.
This investigational therapy fuses IL-2 with a specific mutation to the Fc end of the antibody.
The resulting fusion protein not only has a longer half-life, but also tends to bind to high-affinity receptors
.
This allows it to promote the proliferation of Treg cells, thereby restoring the immune balance in patients with autoimmune diseases
.
It is currently in Phase 2b clinical trials for the treatment of patients with systemic lupus erythematosus (SLE) and ulcerative colitis
.
Image source: Preliminary results from Amgen.
com in SLE patients show that efavaleukin alfa selectively expands Treg cells in the bloodstream
.
Polyethylene glycol-modified IL-2 Coupling polyethylene glycol (PEG) on the surface of IL-2 protein can prolong the half-life of IL-2 protein
.
By controlling the position and quantity of polyethylene glycol coupling on the surface of IL-2, IL-2 analogs that tend to bind to high-affinity receptors or medium-affinity receptors can be constructed
.
For example, bempegaldesleukin (NKTR-214) developed by Nektar Therapeutics has an average of 6 PEG chains coupled near the interface where IL-2 binds to CD25
.
This PEG modification effectively blocked its binding to the high-affinity IL-2R receptor, making bempegaldesleukin more inclined to activate CD8-positive memory T cells and NK cells
.
Bristol-Myers Squibb and Nektar have entered into an R&D agreement to evaluate bempegaldesleukin in combination with the anti-PD-1 antibody Opdivo in multiple tumor types
.
There are currently 5 clinical trials with registration potential in progress, but Bristol-Myers Squibb recently announced that a Phase 3 clinical trial of this combination therapy in melanoma did not meet the primary endpoint
.
A defect of some PEG-modified IL-2 (such as bempegaldesleukin) is that the PEG-modified sites are not consistent between different protein molecules, which may cause some IL-2 proteins to fail to selectively activate CD8-positive T cells and NK cells, thereby affecting the efficacy of candidate therapies
.
To solve this problem, some biotech companies introduced unnatural amino acids on the surface of IL-2 and coupled PEG chains to these unnatural amino acids
.
This method can precisely locate the conjugation site of PEG on the surface of IL-2, possibly generating more homogenous IL-2 analogs
.
Sanofi's SAR444245 (formerly THOR707) is one such IL-2 analog
.
By introducing unnatural amino acids on the interface between IL-2 protein and CD25, it precisely connects PEG chains on the surface of IL-2, and blocks the binding of IL-2 and CD25
.
Sanofi said the IL-2 analog may have "best-in-class" potential
.
It is currently being tested in multiple Phase 2 clinical trials, in combination with PD-1 inhibitors or other anti-cancer therapies, in a number of different cancer types
.
▲Introduction to SAR444245 (Image source: Sanofi official website) IL-2 immune complex IL-2 combined with anti-IL-2 monoclonal antibody to form a complex also prolongs the half-life of IL-2 protein and regulates the receptor binding selection of IL-2 a way of sex
.
Monoclonal antibodies targeting IL-2 can block the binding of IL-2 to CD25 or CD122 by binding to specific epitopes of IL-2, thereby giving them selective binding to high-affinity IL-2R or medium-affinity IL-2R ability to combine
.
Anaveon's selective IL-2R agonist ANV419 follows this model
.
It fuses a monoclonal antibody targeting the binding site of IL-2 to CD25 to IL-2, thereby blocking the binding of IL-2 to CD25
.
This fusion protein still has the ability to bind to the medium-affinity IL-2R receptor, so it can selectively activate CD8-positive memory T cells and NK cells
.
Binding to the antibody also extends its half-life
.
▲A schematic diagram of the mechanism of action of ANV419 (Image source: Anaveon's official website) Anaveon completed a Series B financing of about US$120 million at the end of last year, and the investors included the venture capital department of Pfizer and Novartis
.
IL-2-CD25 fusion protein Another strategy to selectively bind IL-2 to the medium-affinity IL-2R receptor is to fuse IL-2 with soluble CD25, and the resulting fusion protein can no longer bind to cell surface CD25.
Binding, thereby blocking the binding to high-affinity IL-2R
.
One such fusion protein is nemvaleukin alfa (ALKS 4230) developed by Alkermes
.
It does not activate Treg cells while activating CD8-positive memory T cells and NK cells by selectively binding to the medium-affinity IL-2R receptor
.
▲The mechanism of action of Nemvaleukin alfa (Image source: Reference [7]) This investigational therapy has obtained two fast-track qualifications granted by the US FDA, which are used in combination with anti-PD-1 antibodies to treat platinum-containing chemotherapy resistance.
Ovarian cancer, and mucosal melanoma
.
Clinical development has entered into Phase 2 and Phase 3 clinical trials
.
The authors of a review of the pros and cons of different strategies for modifying IL-2 suggest that these different strategies for modifying IL-2 also have their own pros and cons
.
For example, IL-2 mutants can effectively confer selectivity to IL-2 protein binding to specific IL-2Rs by changing the amino acids on the surface of IL-2.
2 mutants are considered foreign proteins by the body's immune system, triggering an immune response against IL-2 mutants, thereby reducing the efficacy of potential therapies
.
PEGylation of IL-2, IL-2 immune complexes and IL-2-CD25 fusion proteins could theoretically confer selectivity to IL-2 without introducing mutations, thereby reducing the immunogenicity of candidate therapies
.
However, they also have their own shortcomings.
If the site of PEG modification is uncertain, it may lead to product heterogeneity and affect the overall therapeutic effect
.
The IL-2 immune complex may release free IL-2 in the blood circulation, leading to stimulation of other unwanted immune cells
.
Although we have a variety of strategies to engineer IL-2 to give them the ability to selectively activate anticancer immune responses or suppress overactive immune responses, which strategy is safer and more effective still needs follow-up clinical trials to verify
.
A variety of IL-2 analogs are currently in clinical development, and the review authors say that in the coming years we will see whether these advances in IL-2 engineering can lead to effective anti-cancer and innovative treatments for autoimmune diseases
.
Reference: [1] Hernandez et al.
, (2022).
Engineering IL-2 for immunotherapy of autoimmunity and cancer.
Nature Reviews Immunology, https://doi.
org/10.
1038/s41577-022-00680-w[2] Amgen Business Review.
Retrieved March 9, 2022, from https://investors.
amgen.
com/static-files/6d823d7d-2fd1-405a-8c0e-22aa91bee682[3] Nektar Therapeutics Corporate Presentation.
Retrieved March 9, 2022, from https ://ir.
nektar.
com/static-files/7818281a-1882-4952-9ebc-7680643f109a[4] Sanofi Oncology ASCO Event.
Retrieved March 9, 2022, from https:// /Project/One-Sanofi-Web/Websites/Global/Sanofi-COM/Home/common/docs/investors/2021_06_04_ASCO_Slides_FINAL.
pdf?la=en&hash=A961668213E13C37545571B90B46939B[5] Anaveon.
Retrieved March 9, 2022, from https:// anaveon.
com/our-approach/[6] Alkermes to Present Data on Nemvaleukin Alfa at the Society of Gynecologic Oncology 2022 Annual Meeting on Women's Cancer.
Retrieved March 9, 2022, from https:// alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/10.
1124/jpet.
121.
000612 Disclaimer Statement: WuXi AppTec content team focuses on introducing global biomedical health research progresscom/news-releases/alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/ 10.
1124/jpet.
121.
000612 Disclaimer: WuXi AppTec content team focuses on introducing global biomedical health research progresscom/news-releases/alkermes-to-present-data-on-nemvaleukin-alfa-at-the-society-of-gynecologic-oncology-2022-annual-meeting-on-womens-cancer-301492162.
html[7] Lopes, et al.
, (2021).
Pharmacokinetics and Pharmacodynamic Effects of Nemvaleukin Alfa, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, in Cynomolgus Monkeys.
Journal of Pharmacology and Experimental Therapeutics, https://doi.
org/ 10.
1124/jpet.
121.
000612 Disclaimer: WuXi AppTec content team focuses on introducing global biomedical health research progress
.
This article is for information exchange purposes only, and the views expressed in this article do not represent WuXi AppTec's position, nor do they represent WuXi AppTec's support or opposition to the views expressed in this article
.
This article is also not a treatment plan recommendation
.
For guidance on treatment options, please visit a regular hospital
.
