As the growth of potential drug or test agent partners for combination therapies continues, so does the need for a strategic approach to design effective and safe combinations. The BioMAP® Combo ELECT Service allows statistical evaluation of combination and monotherapies to inform on potential drug synergies, antagonisms, adverse effects, and dosing guidance in a nominated BioMAP disease model of interest. Each agent is analyzed individually, and then statistically compared against a combination array of the two serially diluted agents. Choose any BioMAP system to test both individual agents and a 4×4 concentration matrix of combinations.
Applications for Drug Discovery with Combo ELECT
- Find drug combinations with novel, additive, or antagonistic effects
- Rescue “at risk” compounds due to lack of efficacy or negative early chemical trial results
- Expand the therapeutic utility of existing clinical drugs and drugs in development
- Anticipate potential adverse events due to drug combinations for smarter clinical trial design
Combination Therapies in BioMAP Systems
Combination Therapies in BioMAP Systems Reflect, with Potential to Predict, Clinical Observations
BioMAP colorectal carcinoma (CRC) systems consist of co-cultures of human primary tissue cells (stromal or vascular) with immune cells and the HT29 tumor cell line stimulated with T cell receptor agonists. These systems recapitulate host tissue-immune-tumor microenvironment (TME) biology in vitro to provide translationally relevant impacts of individual test agents or combinations on a panel of protein-based biomarkers, including immune cytokines, relevant for IO strategies.
Testing Statistical Differentiation
Figure 1. The BioMAP Combo ELECT service was used with the VascHT29 system to demonstrate that pembrolizumab synergizes with the microtubule stabilizing drug paclitaxel, but not with the indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor epacadostat. A. Pembrolizumab (red) and paclitaxel (blue) both increase cytokine levels (plot) when tested as individual agents. Combination treatment (black) results in greater cytokine increase, indicating enhanced immune function (bar chart), consistent with clinical findings. B. The profile of epacadostat is largely inactive (blue), with no synergy observed between pembrolizumab and epacadostat (black).
Schematic of Combination Testing Strategy
Figure 2. A 4×4 combination array is created to test all mixtures of two serially diluted single test agents or molecules, in triplicate, in select BioMAP systems (35+ human biology and disease model systems available through the BioMAP Combo ELECT service).
A 4×4 combination array is created to test all mixtures of two serially diluted single test agents or compounds, in triplicate, in select BioMAP systems (35+ human biology and disease model systems available through BioMAP Combo ELECT).
| Combo ELECT Combination Study Service | |
|---|---|
| Service |
|
| Description |
|
| Deliverables |
|
| System Name | Disease & Tissue Relevance | Human Primary Cell Types | Translation Readouts |
|---|---|---|---|
| 3C | Cardiovascular Disease, Chronic Inflammation | Venular endothelial cells | CCL2/MCP-1, CD106/VCAM-1, CD141/Thrombomodulin, CD142/Tissue Factor, CD54/ICAM-1, CD62E/E-Selectin, CD87/uPAR, CXCL8/IL-8, CXCL9/MIG, HLA-DR, Proliferation, SRB |
| 4H | Asthma, Allergy, Autoimmunity | Venular endothelial cells | CCL2/MCP-1, CCL26/Eotaxin-3, CD106/VCAM-1, CD62P/P-Selectin, CD87/uPAR, SRB, VEGFR2 |
| BE3C | Lung Inflammation, COPD | Bronchial epithelial cells | CD54/ICAM-1, CD87/uPAR, CXCL10/IP-10, CXCL11/I-TAC, CXCL8/IL-8, CXCL9/MIG, EGFR, HLA-DR, IL-1α, Keratin 8/18, MMP-1, MMP-9, PAI-1, SRB, tPA, uPA |
| BENo | Epithelial Biology, Lung Biology | Bronchial epithelial cells | CCL26/Eotaxin-3, CD54/ICAM-1, CD87/uPAR, CXCL10/IP-10, CXCL11/I-TAC, CXCL8/IL-8, CXCL9/MIG, EGFR, HLA-DR, IL-1α, Keratin 8/18, MMP-1, MMP-9, PAI-1, SRB, tPA, uPA |
| BF4T | Asthma, Allergy, Fibrosis, Lung Inflammation | Bronchial epithelial cells + Dermal fibroblasts | CCL2/MCP-1, CCL26/Eotaxin-3, CD106/VCAM-1, CD54/ICAM-1, CD90, CXCL8/IL-8, IL-1α, Keratin 8/18, MMP-1, MMP-3, MMP-9, PAI-1, SRB, tPA, uPA |
| BFNo | Asthma, Allergy, Fibrosis, Lung Inflammation | Bronchial epithelial cells + Dermal fibroblasts | CCL2/MCP-1, CCL26/Eotaxin-3, CD106/VCAM-1, CD54/ICAM-1, CD90, CXCL8/IL-8, IL-1α, Keratin 8/18, MMP-1, MMP-3, MMP-9, PAI-1, SRB, tPA, uPA |
| BT | Asthma, Allergy, Oncology, Autoimmunity | B cells + Peripheral blood mononuclear cells | B cell Proliferation, PBMC cytotoxicity, Secreted IgG, sIL-17A, sIL-17F, sIL-2, sIL-6, sTNFα |
| BTNo | Asthma, Allergy, Oncology, Autoimmunity | B cells + Peripheral blood mononuclear cells | B cell Proliferation, PBMC cytotoxicity, Secreted IgG, sIL-17A, sIL-17F, sIL-2, sIL-6, sTNFα |
| CASM3C | Cardiovascular Inflammation, Restenosis | Coronary artery smooth muscle cells | CCL2/MCP-1, CD106/VCAM-1, CD141/Thrombomodulin, CD142/Tissue Factor, CD87/uPAR, CXCL8/IL-8, CXCL9/MIG, HLA-DR, IL-6, LDLR, M-CSF, PAI-1, Proliferation, Serum Amyloid A, SRB |
| CASMNo | Vascular Biology | Coronary artery smooth muscle cells | CCL2/MCP-1, CD106/VCAM-1, CD141/Thrombomodulin, CD142/Tissue Factor, CD87/uPAR, CXCL8/IL-8, CXCL9/MIG, HLA-DR, IL-6, LDLR, M-CSF, PAI-1, Proliferation, Serum Amyloid A, SRB |
| HDF3CGF | Fibrosis, Chronic Inflammation | Dermal fibroblasts | CCL2/MCP-1, CD106/VCAM-1, CD54/ICAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, CXCL8/IL-8, CXCL9/MIG, EGFR, M-CSF, MMP-1, PAI-1, Proliferation_72hr, SRB, TIMP-1, TIMP-2 |
| HDFNo | Fibroblast Biology | Dermal fibroblasts | CCL2/MCP-1, CD106/VCAM-1, CD54/ICAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, CXCL8/IL-8, CXCL9/MIG, EGFR, M-CSF, MMP-1, PAI-1, Proliferation_72hr, SRB, TIMP-1, TIMP-2 |
| HDFPNo | Immune Biology | Dermal fibroblasts + Peripheral blood mononuclear cells | CCL2/MCP-1, CD106/VCAM-1, Collagen I, CXCL10/IP-10, CXCL8/IL-8, CXCL9/MIG, M-CSF, MMP-1, sIL-2, sIL-6, sIL-10, sIL-17A, sIL-17F, SRB, sTGFβ1, sTNFα, sVEGF |
| HDFSAg | Autoimmune Disease, Chronic Inflammation, Rheumatoid Arthritis | Dermal fibroblasts + Peripheral blood mononuclear cells | CCL2/MCP-1, CD106/VCAM-1, Collagen I, CXCL10/IP-10, CXCL8/IL-8, CXCL9/MIG, M-CSF, MMP-1, sIL-2, sIL-6, sIL-10, sIL-17A, sIL-17F, SRB, sTGFβ1, sTNFα, sVEGF |
| HNo | Vascular Biology | Venular endothelial cells | CCL2/MCP-1, CD106/VCAM-1, CD141/Thrombomodulin, CD142/Tissue Factor, CD38, CD40, CD62E/E-Selectin, CD69, CXCL8/IL-8, CXCL9/MIG, M-CSF, sPGE2, SRB, sTNFα |
| HPNo | Vascular Biology, Immune Biology | Peripheral blood mononuclear cells + Venular endothelial cells | CCL2/MCP-1, CD54/ICAM-1, CXCL10/IP-10, CXCL8/IL-8, CXCL9/MIG, IL-1α, MMP-9, PAI-1, SRB, TIMP-2, uPA |
| KF3CT | Psoriasis, Dermatitis, Skin Biology | Keratinocytes + Dermal fibroblasts | CCL2/MCP-1, CD54/ICAM-1, CXCL10/IP-10, CXCL8/IL-8, CXCL9/MIG, IL-1α, MMP-9, PAI-1, SRB, TIMP-2, uPA |
| KFNo | Skin Biology | Keratinocytes + Dermal fibroblasts | CCL2/MCP-1, CD106/VCAM-1, CD141/Thrombomodulin, CD142/Tissue Factor,CD40, CD62E/E-Selectin, CD69, CXCL8/IL-8, IL-1α, M-CSF, sPGE2, SRB, sTNFα |
| LPS | Cardiovascular Disease, Chronic Inflammation | Peripheral blood mononuclear cells + Venular endothelial cells | α-SM Actin, bFGF, CD106/VCAM-1, Collagen I, Collagen III, Collagen IV, CXCL8/IL-8, Decorin, MMP-1, PAI-1, SRB, TIMP-1 |
| MyoF | Fibrosis, Chronic Inflammation, Wound Healing, Matrix Remodeling | Lung fibroblasts | α-SM Actin, bFGF, CD106/VCAM-1, Collagen I, Collagen III, Collagen IV, CXCL8/IL-8, Decorin, MMP-1, PAI-1, SRB, TIMP-1 |
| MyoFNo | Fibroblast Biology | Lung fibroblasts | α-SM Actin, bFGF, CD106/VCAM-1, Collagen I, Collagen III, Collagen IV, CXCL8/IL-8, Decorin, MMP-1, PAI-1, SRB, TIMP-1 |
| REMyoF | Renal Fibrosis, Chronic Inflammation, Wound Healing, Matrix Remodeling | Renal proximal tubule epithelial cells + Lung fibroblasts | α-SM Actin, CCL2/MCP-1, CD106/VCAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, E-Cadherin, EGFR, Keratin 8/18, M-CSF, MMP-1, MMP-9, N-Cadherin, PAI-1, sIL-6, sIL-8, SRB, sVEGF, TIMP-1, tPA, uPA |
| REMyoFNo | Renal Fibrosis | Renal proximal tubule epithelial cells + Lung fibroblasts | α-SM Actin, CCL2/MCP-1, CD106/VCAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, E-Cadherin, EGFR, Keratin 8/18, M-CSF, MMP-1, MMP-9, N-Cadherin, PAI-1, sIL-6, sIL-8, SRB, sVEGF, TIMP-1, tPA, uPA |
| SAEMyoF | Pulmonary Fibrosis, Chronic Inflammation, Wound Healing, Matrix Remodeling | Small airway epithelial cells + Lung fibroblasts | α-SM Actin, CCL2/MCP-1, CD106/VCAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, E-Cadherin, EGFR, M-CSF, MMP-1, MMP-9, N-Cadherin, PAI-1, sIL-6, sIL-8, SRB, sVEGF, TIMP-1, uPA |
| SAEMyoFNo | Pulmonary Fibrosis, Inflammation, Wound Healing, Matrix Remodeling | Small airway epithelial cells + Lung fibroblasts | α-SM Actin, CCL2/MCP-1, CD106/VCAM-1, Collagen I, Collagen III, CXCL10/IP-10, CXCL11/I-TAC, E-Cadherin, EGFR, M-CSF, MMP-1, MMP-9, N-Cadherin, PAI-1, sIL-6, sIL-8, SRB, sVEGF, TIMP-1, uPA |
| SAg | Autoimmune Disease, Chronic Inflammation | Peripheral blood mononuclear cells + Venular endothelial cells | CCL2/MCP-1, CD38, CD40, CD62E/E-Selectin, CD69, CXCL8/IL-8, CXCL9/MIG, PBMC cytotoxicity, Proliferation, SRB |
| StroC | Tissue Remodeling, Wound Healing, Inflammation | Primary human fibroblasts + Peripheral blood mononuclear cells | CD106/VCAM-1, CD87/uPAR, CEACAM5/CD66e, Collagen I, Collagen III, CXCL10/IP-10, Keratin 20, MMP-9, PAI-1, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-6, sIL-10, sIL-17A, SRB, sTNFα, sVEGF, TIMP-2, tPA, uPA |
| StroHT29 | CRC Oncology/Immuno- Oncology: Host Stromal-Tumor Microenvironment Biology, Tissue Remodeling, Wound Healing, Inflammation | HT-29 colorectal adenocarcinoma cell line + Primary human fibroblasts + Peripheral blood mononuclear cells | CD106/VCAM-1, CD87/uPAR, CEACAM5/CD66e, Collagen I, Collagen III, CXCL10/IP-10, Keratin 20, MMP-9, PAI-1, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-6, sIL-10, sIL-17A, SRB, sTNFα, sVEGF, TIMP-2, tPA, uPA |
| StroL | Tissue Remodeling, Wound Healing, Inflammation | Primary human fibroblasts + Peripheral blood mononuclear cells | CD106/VCAM-1, CD87/uPAR, Collagen III, CXCL10/IP-10, EGFR, HGF, PAI-1, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-4, sIL-6, sIL-10, sIL-13, sIL-17A, sMDC, sPGE2, SRB, sTNFα, sVEGF, tPA, uPA |
| VascC | Vascular Biology, Inflammation | Primary human endothelial cells + Peripheral blood mononuclear cells | CCL2/MCP-1, CD106/VCAM-1, CD40, CD69, CD87/uPAR, CEACAM5/CD66e, Collagen IV, CXCL9/MIG, CXCL10/IP-10, Keratin 20, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-6, sIL-10, sIL-17A, SRB, sTNFα |
| VascHT29 | CRC Oncology/Immuno- Oncology: Host Vascular- Tumor Microenvironment Biology, Inflammation | HT-29 colorectal adenocarcinoma cell line + Primary human endothelial cells + Peripheral blood mononuclear cells | CCL2/MCP-1, CD106/VCAM-1, CD40, CD69, CD87/uPAR, CEACAM5/CD66e, Collagen IV, CXCL9/MIG, CXCL10/IP-10, Keratin 20, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-6, sIL-10, sIL-17A, SRB, sTNFα |
| VascL | Vascular Biology, Inflammation | Primary human endothelial cells + Peripheral blood mononuclear cells | CCL2/MCP-1, CD106/VCAM-1, CD40, CD69, CD87/uPAR, CXCL10/IP-10, PAI-1, PBMC cytotoxicity, sGranzyme B, sIFNγ, sIL-2, sIL-4, sIL-6, sIL-10, sIL-13, sIL-17A, sMDC, SRB, sTNFα |
| lMphg | Cardiovascular Inflammation, Restenosis, Chronic Inflammation | Venular endothelial cells + Macrophages | CCL2/MCP-1, CCL3/MIP-1α, CD106/VCAM-1, CD40, CD62E/E-Selectin, CD69, CXCL8/IL-8, IL-1α, M-CSF, sIL-10, SRB, SRB-Mphg |
| lMphgNo | Vascular Biology, Immune Biology | Venular endothelial cells + M1 macrophages | CCL2/MCP-1, CCL3/MIP-1α, CD106/VCAM-1, CD40, CD62E/E-Selectin, CD69, CXCL8/IL-8, IL-1α, M-CSF, SRB, SRB-Mphg |
| lTH2 | Asthma, Allergy, Oncology | Venular endothelial cells + TH2 blasts | CCL2/MCP-1, CCL26/Eotaxin-3, CD106/ VCAM-1, CD38, CD40, CD62E/E-Selectin, CD62P/P-Selectin, CD69, CD87/uPAR, Collagen IV, CXCL8/IL-8, CXCL9/MIG, PBMC cytotoxicity, sIL-17A, sIL-17F, SRB |
| lTH2No | Vascular Biology, Immune Biology | Venular endothelial cells + TH2 blasts | CCL2/MCP-1, CCL26/Eotaxin-3, CD106/VCAM-1, CD38, CD40, CD62E/E-Selectin, CD62P/P-Selectin, CD69, CD87/uPAR, Collagen IV, CXCL8/IL-8, CXCL9/MIG, PBMC cytotoxicity, sIL-17A, sIL-17F, SRB |
| *System names terminating with No indicate no stimulation; system names beginning with ital l (l) indicate low levels of stimulation | |||
Watch the webinar,Enabling Development of Cancer Immunotherapy Drugs.
