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The use of CD3 bispecific antibodies to treat cancer is an approved treatment plan for some hematomas, and a large number of clinical studies have been conducted on the treatment of solid tumors
.
However, the treatment of solid tumors faces more obstacles, such as increased off-target toxicity, scarce T cell infiltration, and the existence of immunosuppressive tumor microenvironment, which all affect the safety of CD3-bispecific antibody therapy and limit Curative effect
.
There are many strategies to expand the application window of TAA-CD3 double antibodies, such as conditional activation of antibodies, which specifically remove the shielding peptides on CD3 antibodies through urokinase and metalloproteinases in the tumor microenvironment to activate CD3 antibodies; in addition, by optimizing the CD3 antibody Affinity or the development of antibodies to new CD3ε epitopes are also the main strategies to reduce the release of cytokines in the application of CD3 double antibodies
.
This article mainly summarizes the preclinical results of several TAA-CD3 double antibodies developed by reducing the affinity of CD3
.
Genentech’s HER2-CD3 Genentech’s CD3 double antibody has a long history of research, and a variety of CD3 double antibody platforms have also been established
.
In 2018, a study on the effect of CD3 affinity on antibody tissue distribution was reported
.
In the study, HER2-CD3 double antibodies with different CD3 affinities were developed.
It was found that the high-affinity CD3 double antibodies were mainly distributed in secondary lymphoid organs, destroying the distribution of HER2+ tumor tissue.
When the affinity of CD3 was 50nM, the tumor tissue distribution was obvious Increase
.
Tissue distribution of different CD3 variants with different affinity result
.
By mutating the amino acids in the CDR region to the Germline amino acids, CD3 antibodies with different affinities were obtained
.
The affinity of Bivalent CD3M is 7.
25E-09, and the affinity of Bivalent CD3W is 8.
39E-07
.
The endocytosis efficiency of antibodies with different affinities was detected by a biosensor quantitative method, and it was found that Bivalent CD3M has more antibodies entering the lysosome than Bivalent CD3W
.
Although Bivalent CD3W at the mutation site of different CD3 affinity antibodies greatly reduces the binding of Jurkat cells, and the activity based on the NFAT-Luc reporter gene is also significantly reduced, but the different affinity antibodies can activate PBMC to MUC16+ tumor cells OVCAR- 3 Achieve complete destruction
.
In the human PBMC humanized mouse model experiment, there is no significant difference in the inhibitory activity of the two affinity CD3 double antibodies against OVCAR-3 tumors, but the cytokines-TNFα and IL-2 in the serum of the Bivalent CD3W double antibodies have significant differences Lower
.
Consistent with Genentech’s HER2-CD3 double antibody results, the low-affinity CD3 double antibody also showed obvious tumor tissue distribution
.
The binding of monovalent CD3 antibody to Jurkat cells.
The MUC16 of OVCAR-3 specifically activates the NFAT reporter gene of Jurkat cells.
The killing activity of PBMC on OVCAR-3 cells.
The in vivo efficacy and cytokine release of MUC16-CD3 double antibodies with different affinities in a mouse tumor model The tissue distribution of Amgen’s AMG757 CD3 double antibody for solid tumor treatment is mainly based on the HLE BiTE platform.
At the same time, it recently acquired the biotechnology company Teneobio, which has developed a CD3 antibody that specifically recognizes CD3δε without binding to CD3γε, clinically Previous experiments proved that the new epitope CD3 double antibody can greatly reduce the release of cytokines
.
The AMG757 structure is an HLE BiTE structure double antibody, which has a longer half-life than BiTE, and has an affinity for human CD3 of about 15 nM.
It has a very high T cell killing activity against DLL3+ SHP-77, and it does not kill DLL3-NCI-H460 cells
.
In the in vivo efficacy experiment, it has significant tumor suppressor activity on SHP-77 and NCI-H82
.
The AMG757 reported by the ASCO meeting this year is a DLL3-CD3 dual antibody.
The overall response rate ORR in the treatment of small cell lung cancer is 20%, and the disease control rate DCR is 47%.
It is a publicly disclosed CD3 dual antibody that has relatively high efficacy in the treatment of solid tumors.
Of antibodies
.
The molecular structure and cellular activity of AMG757.
The in vivo efficacy of AMG757 in different tumor models.
Boan Bio's CEA-CD3 Boan Bio has developed a CEA-CD3 double antibody for the treatment of colorectal cancer, which reduces the affinity of the CD3 antibody through mutations
.
The double antibody structure is a double antibody of CD3 scFv fused to the light chain bivalent CD3 double antibody.
The mutant CD3 double antibody greatly reduces the binding of T cells, and at the same time, the reduced affinity does not affect the in vitro killing activity of PBMC on tumor cells.
It can also effectively inhibit the growth of tumor cells
.
Summary of the structure and mutation site of CD3 antibody.
By specifically reducing the affinity of CD3 antibody, many pharmaceutical companies have developed CD3 bispecific antibodies that reduce the release of cytokines, which improves the tumor tissue without losing efficacy.
Distribution, expand the dosing window
.
Compared with conditionally activated CD3 double antibodies, screening of shielding peptides is required, and the screening of CD3 double antibodies with reduced affinity is simpler.
I believe that as more and more CD3 double antibodies are published in the treatment of solid tumors, it is sure to see CD3 double antibodies in Bright prospects in the treatment of solid tumors
.
References: 1.
Mandikian D, Takahashi N, Lo AA, et al.
Relative Target Affinities of T Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model.
Mol Cancer Ther.
2018; 17(4):776-785 DOI: 10.
1158/1535-7163.
MCT-17-0657.
2.
Haber L, Olson K, Kelly MP, et al.
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.
Sci Rep.
2021; 11: 14397.
doi: 10.
1038/s41598-021-93842-0.
3.
Giffin MJ, Cooke K, Lobenhofer EK, et al.
AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.
Clin Cancer Res.
2021;27(5):1526-1537.
doi: 10.
1158/1078-0432.
CCR-20-2845.
4.
Wang N, Patel H, Schneider I, et al.
An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers.
Antib Ther.
2021;4(2):90-100.
doi: 10.
1093/abt/tbab009.
.
However, the treatment of solid tumors faces more obstacles, such as increased off-target toxicity, scarce T cell infiltration, and the existence of immunosuppressive tumor microenvironment, which all affect the safety of CD3-bispecific antibody therapy and limit Curative effect
.
There are many strategies to expand the application window of TAA-CD3 double antibodies, such as conditional activation of antibodies, which specifically remove the shielding peptides on CD3 antibodies through urokinase and metalloproteinases in the tumor microenvironment to activate CD3 antibodies; in addition, by optimizing the CD3 antibody Affinity or the development of antibodies to new CD3ε epitopes are also the main strategies to reduce the release of cytokines in the application of CD3 double antibodies
.
This article mainly summarizes the preclinical results of several TAA-CD3 double antibodies developed by reducing the affinity of CD3
.
Genentech’s HER2-CD3 Genentech’s CD3 double antibody has a long history of research, and a variety of CD3 double antibody platforms have also been established
.
In 2018, a study on the effect of CD3 affinity on antibody tissue distribution was reported
.
In the study, HER2-CD3 double antibodies with different CD3 affinities were developed.
It was found that the high-affinity CD3 double antibodies were mainly distributed in secondary lymphoid organs, destroying the distribution of HER2+ tumor tissue.
When the affinity of CD3 was 50nM, the tumor tissue distribution was obvious Increase
.
Tissue distribution of different CD3 variants with different affinity result
.
By mutating the amino acids in the CDR region to the Germline amino acids, CD3 antibodies with different affinities were obtained
.
The affinity of Bivalent CD3M is 7.
25E-09, and the affinity of Bivalent CD3W is 8.
39E-07
.
The endocytosis efficiency of antibodies with different affinities was detected by a biosensor quantitative method, and it was found that Bivalent CD3M has more antibodies entering the lysosome than Bivalent CD3W
.
Although Bivalent CD3W at the mutation site of different CD3 affinity antibodies greatly reduces the binding of Jurkat cells, and the activity based on the NFAT-Luc reporter gene is also significantly reduced, but the different affinity antibodies can activate PBMC to MUC16+ tumor cells OVCAR- 3 Achieve complete destruction
.
In the human PBMC humanized mouse model experiment, there is no significant difference in the inhibitory activity of the two affinity CD3 double antibodies against OVCAR-3 tumors, but the cytokines-TNFα and IL-2 in the serum of the Bivalent CD3W double antibodies have significant differences Lower
.
Consistent with Genentech’s HER2-CD3 double antibody results, the low-affinity CD3 double antibody also showed obvious tumor tissue distribution
.
The binding of monovalent CD3 antibody to Jurkat cells.
The MUC16 of OVCAR-3 specifically activates the NFAT reporter gene of Jurkat cells.
The killing activity of PBMC on OVCAR-3 cells.
The in vivo efficacy and cytokine release of MUC16-CD3 double antibodies with different affinities in a mouse tumor model The tissue distribution of Amgen’s AMG757 CD3 double antibody for solid tumor treatment is mainly based on the HLE BiTE platform.
At the same time, it recently acquired the biotechnology company Teneobio, which has developed a CD3 antibody that specifically recognizes CD3δε without binding to CD3γε, clinically Previous experiments proved that the new epitope CD3 double antibody can greatly reduce the release of cytokines
.
The AMG757 structure is an HLE BiTE structure double antibody, which has a longer half-life than BiTE, and has an affinity for human CD3 of about 15 nM.
It has a very high T cell killing activity against DLL3+ SHP-77, and it does not kill DLL3-NCI-H460 cells
.
In the in vivo efficacy experiment, it has significant tumor suppressor activity on SHP-77 and NCI-H82
.
The AMG757 reported by the ASCO meeting this year is a DLL3-CD3 dual antibody.
The overall response rate ORR in the treatment of small cell lung cancer is 20%, and the disease control rate DCR is 47%.
It is a publicly disclosed CD3 dual antibody that has relatively high efficacy in the treatment of solid tumors.
Of antibodies
.
The molecular structure and cellular activity of AMG757.
The in vivo efficacy of AMG757 in different tumor models.
Boan Bio's CEA-CD3 Boan Bio has developed a CEA-CD3 double antibody for the treatment of colorectal cancer, which reduces the affinity of the CD3 antibody through mutations
.
The double antibody structure is a double antibody of CD3 scFv fused to the light chain bivalent CD3 double antibody.
The mutant CD3 double antibody greatly reduces the binding of T cells, and at the same time, the reduced affinity does not affect the in vitro killing activity of PBMC on tumor cells.
It can also effectively inhibit the growth of tumor cells
.
Summary of the structure and mutation site of CD3 antibody.
By specifically reducing the affinity of CD3 antibody, many pharmaceutical companies have developed CD3 bispecific antibodies that reduce the release of cytokines, which improves the tumor tissue without losing efficacy.
Distribution, expand the dosing window
.
Compared with conditionally activated CD3 double antibodies, screening of shielding peptides is required, and the screening of CD3 double antibodies with reduced affinity is simpler.
I believe that as more and more CD3 double antibodies are published in the treatment of solid tumors, it is sure to see CD3 double antibodies in Bright prospects in the treatment of solid tumors
.
References: 1.
Mandikian D, Takahashi N, Lo AA, et al.
Relative Target Affinities of T Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model.
Mol Cancer Ther.
2018; 17(4):776-785 DOI: 10.
1158/1535-7163.
MCT-17-0657.
2.
Haber L, Olson K, Kelly MP, et al.
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.
Sci Rep.
2021; 11: 14397.
doi: 10.
1038/s41598-021-93842-0.
3.
Giffin MJ, Cooke K, Lobenhofer EK, et al.
AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.
Clin Cancer Res.
2021;27(5):1526-1537.
doi: 10.
1158/1078-0432.
CCR-20-2845.
4.
Wang N, Patel H, Schneider I, et al.
An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers.
Antib Ther.
2021;4(2):90-100.
doi: 10.
1093/abt/tbab009.
