TUMOR-SPECIFIC GLYCOSYLATED CD43 IS A NOVEL AND HIGHLY SPECIFIC TARGET FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME
(Abstract release date: 05/19/16)
EHA Library. Hazenberg M. 06/11/16; 135267; S511
Dr. Mette Hazenberg
Contributions
Contributions
Abstract
Abstract: S511
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C14
Background
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Even with intensive treatment regimens less than 50% of patients can be cured, and for the majority of patients - those over 65 years of age and/or patients with comorbidities - such intensive regimens are not feasible. Novel therapeutic approaches such as immunotherapy directed against a highly specific tumor target are highly needed.
Aims
The aim of our study was to identify novel therapeutic antibodies that are highly specific for AML and to discover novel tumor-specific antigens, widely expressed on AML and MDS but not on healthy hematopoietic and non-hematopoietic cells.
Methods
For this we made use of the oldest human tumor immunology model with proven efficacy available: an allogeneic HSCT patient with a potent graft versus AML allo-immune response. From this patient we isolated CD27+ IgG+ memory B lymphocytes and transduced these cells with Bcl-6 and Bcl-xL, thereby generating pre-plasmablast B cell clones that produce abundant antibodies. Supernatants of these B cell clones were used to screen for binding to surface antigens on the AML cell line THP-1.
Results
We identified an IgG1 antibody, AT14-013, that specifically interacted with AML cell lines THP-1, MOLM-13, SH-2 and others, and with leukemic blasts isolated from newly diagnosed AML and MDS patients from our clinic. AT14-013 did not interact with healthy hematopoietic and non-hematopoietic cells. This antibody was of donor origin and was antigen experienced as it contained 26/11 somatic hypermutations in the heavy and light chains, respectively. Target identification using mass spectrometry analysis and epitope mapping strategies with FLAG-tagged truncated variants of CD43 expressed by THP-1 that we created revealed CD43 as the target. CD43 is expressed by all hematopoietic cells, but AT14-013 targeted a specific, sialylated epitope on CD43 that is uniquely and widely expressed on all types of AML, as illustrated by its reactivity with blasts of each of 48 randomly selected AML and MDS patients in our clinic. AT14-013 induced antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity of AML cell lines and primary blasts.
Conclusion
We have identified onco-sialylated CD43 (CD43os) as a novel tumor-specific target that is widely expressed on AML and MDS blasts. Antibodies against this target have high potential as therapeutic antibodies, either as a naked antibody or manufactured into an antibody-drug conjugate, bispecific T cell engager or CAR (chimeric antigen receptor) T cell.
Session topic: Gene therapy, cellular immunotherapy and vaccination
Keyword(s): Acute myeloid leukemia, Antibody targeting, Immune therapy, MDS/AML
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C14
Background
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Even with intensive treatment regimens less than 50% of patients can be cured, and for the majority of patients - those over 65 years of age and/or patients with comorbidities - such intensive regimens are not feasible. Novel therapeutic approaches such as immunotherapy directed against a highly specific tumor target are highly needed.
Aims
The aim of our study was to identify novel therapeutic antibodies that are highly specific for AML and to discover novel tumor-specific antigens, widely expressed on AML and MDS but not on healthy hematopoietic and non-hematopoietic cells.
Methods
For this we made use of the oldest human tumor immunology model with proven efficacy available: an allogeneic HSCT patient with a potent graft versus AML allo-immune response. From this patient we isolated CD27+ IgG+ memory B lymphocytes and transduced these cells with Bcl-6 and Bcl-xL, thereby generating pre-plasmablast B cell clones that produce abundant antibodies. Supernatants of these B cell clones were used to screen for binding to surface antigens on the AML cell line THP-1.
Results
We identified an IgG1 antibody, AT14-013, that specifically interacted with AML cell lines THP-1, MOLM-13, SH-2 and others, and with leukemic blasts isolated from newly diagnosed AML and MDS patients from our clinic. AT14-013 did not interact with healthy hematopoietic and non-hematopoietic cells. This antibody was of donor origin and was antigen experienced as it contained 26/11 somatic hypermutations in the heavy and light chains, respectively. Target identification using mass spectrometry analysis and epitope mapping strategies with FLAG-tagged truncated variants of CD43 expressed by THP-1 that we created revealed CD43 as the target. CD43 is expressed by all hematopoietic cells, but AT14-013 targeted a specific, sialylated epitope on CD43 that is uniquely and widely expressed on all types of AML, as illustrated by its reactivity with blasts of each of 48 randomly selected AML and MDS patients in our clinic. AT14-013 induced antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity of AML cell lines and primary blasts.
Conclusion
We have identified onco-sialylated CD43 (CD43os) as a novel tumor-specific target that is widely expressed on AML and MDS blasts. Antibodies against this target have high potential as therapeutic antibodies, either as a naked antibody or manufactured into an antibody-drug conjugate, bispecific T cell engager or CAR (chimeric antigen receptor) T cell.
Session topic: Gene therapy, cellular immunotherapy and vaccination
Keyword(s): Acute myeloid leukemia, Antibody targeting, Immune therapy, MDS/AML
Abstract: S511
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C14
Background
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Even with intensive treatment regimens less than 50% of patients can be cured, and for the majority of patients - those over 65 years of age and/or patients with comorbidities - such intensive regimens are not feasible. Novel therapeutic approaches such as immunotherapy directed against a highly specific tumor target are highly needed.
Aims
The aim of our study was to identify novel therapeutic antibodies that are highly specific for AML and to discover novel tumor-specific antigens, widely expressed on AML and MDS but not on healthy hematopoietic and non-hematopoietic cells.
Methods
For this we made use of the oldest human tumor immunology model with proven efficacy available: an allogeneic HSCT patient with a potent graft versus AML allo-immune response. From this patient we isolated CD27+ IgG+ memory B lymphocytes and transduced these cells with Bcl-6 and Bcl-xL, thereby generating pre-plasmablast B cell clones that produce abundant antibodies. Supernatants of these B cell clones were used to screen for binding to surface antigens on the AML cell line THP-1.
Results
We identified an IgG1 antibody, AT14-013, that specifically interacted with AML cell lines THP-1, MOLM-13, SH-2 and others, and with leukemic blasts isolated from newly diagnosed AML and MDS patients from our clinic. AT14-013 did not interact with healthy hematopoietic and non-hematopoietic cells. This antibody was of donor origin and was antigen experienced as it contained 26/11 somatic hypermutations in the heavy and light chains, respectively. Target identification using mass spectrometry analysis and epitope mapping strategies with FLAG-tagged truncated variants of CD43 expressed by THP-1 that we created revealed CD43 as the target. CD43 is expressed by all hematopoietic cells, but AT14-013 targeted a specific, sialylated epitope on CD43 that is uniquely and widely expressed on all types of AML, as illustrated by its reactivity with blasts of each of 48 randomly selected AML and MDS patients in our clinic. AT14-013 induced antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity of AML cell lines and primary blasts.
Conclusion
We have identified onco-sialylated CD43 (CD43os) as a novel tumor-specific target that is widely expressed on AML and MDS blasts. Antibodies against this target have high potential as therapeutic antibodies, either as a naked antibody or manufactured into an antibody-drug conjugate, bispecific T cell engager or CAR (chimeric antigen receptor) T cell.
Session topic: Gene therapy, cellular immunotherapy and vaccination
Keyword(s): Acute myeloid leukemia, Antibody targeting, Immune therapy, MDS/AML
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C14
Background
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Even with intensive treatment regimens less than 50% of patients can be cured, and for the majority of patients - those over 65 years of age and/or patients with comorbidities - such intensive regimens are not feasible. Novel therapeutic approaches such as immunotherapy directed against a highly specific tumor target are highly needed.
Aims
The aim of our study was to identify novel therapeutic antibodies that are highly specific for AML and to discover novel tumor-specific antigens, widely expressed on AML and MDS but not on healthy hematopoietic and non-hematopoietic cells.
Methods
For this we made use of the oldest human tumor immunology model with proven efficacy available: an allogeneic HSCT patient with a potent graft versus AML allo-immune response. From this patient we isolated CD27+ IgG+ memory B lymphocytes and transduced these cells with Bcl-6 and Bcl-xL, thereby generating pre-plasmablast B cell clones that produce abundant antibodies. Supernatants of these B cell clones were used to screen for binding to surface antigens on the AML cell line THP-1.
Results
We identified an IgG1 antibody, AT14-013, that specifically interacted with AML cell lines THP-1, MOLM-13, SH-2 and others, and with leukemic blasts isolated from newly diagnosed AML and MDS patients from our clinic. AT14-013 did not interact with healthy hematopoietic and non-hematopoietic cells. This antibody was of donor origin and was antigen experienced as it contained 26/11 somatic hypermutations in the heavy and light chains, respectively. Target identification using mass spectrometry analysis and epitope mapping strategies with FLAG-tagged truncated variants of CD43 expressed by THP-1 that we created revealed CD43 as the target. CD43 is expressed by all hematopoietic cells, but AT14-013 targeted a specific, sialylated epitope on CD43 that is uniquely and widely expressed on all types of AML, as illustrated by its reactivity with blasts of each of 48 randomly selected AML and MDS patients in our clinic. AT14-013 induced antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity of AML cell lines and primary blasts.
Conclusion
We have identified onco-sialylated CD43 (CD43os) as a novel tumor-specific target that is widely expressed on AML and MDS blasts. Antibodies against this target have high potential as therapeutic antibodies, either as a naked antibody or manufactured into an antibody-drug conjugate, bispecific T cell engager or CAR (chimeric antigen receptor) T cell.
Session topic: Gene therapy, cellular immunotherapy and vaccination
Keyword(s): Acute myeloid leukemia, Antibody targeting, Immune therapy, MDS/AML
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