Peptide Information
General Information of This Peptide
| Peptide ID |
PEP00174
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| Peptide Name |
BT1718 Bicycle peptide
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| Structure |
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| Sequence |
Sar:Ala-Cys-D-Ala]-Asn-Glu-1NAl-(D-Ala)-Cys-Glu-Asp-Phe-Tyr-Asp-tBuGly-Cys
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| Peptide Type |
Cyclic (Bicycle)
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| Receptor Name |
Matrix metalloproteinase-14 (MMP14)
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Receptor Info | ||||
| PDC Transmembrane Types | Cell targeting peptides (CTPs) | |||||
| Formula |
C85H107N17O25S3
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| Isosmiles |
C[C@H](N)C(=O)N[C@H]1CSCc2cc3cc(c2)CSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](Cc2ccc4ccccc4c2)NC(=O)[C@@H](CCC(=O)O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](C)NC1=O)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@H](CC(=O)O)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccc(O)cc1)C(=O)NC(C(=O)O)C(=O)N[C@H](C(C)(C)C)C(=O)N[C@H](C(N)=O)CSC3
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| InChI |
InChI=1S/C85H107N17O25S3/c1-41(86)70(112)99-61-39-129-36-48-26-47-27-49(28-48)37-130-40-62(100-72(114)43(3)89-75(117)57(32-46-16-19-50-14-10-11-15-51(50)29-46)94-73(115)53(22-24-64(105)106)91-77(119)58(33-63(87)104)93-71(113)42(2)90-80(61)122)81(123)92-54(23-25-65(107)108)74(116)97-59(34-66(109)110)78(120)95-55(30-44-12-8-7-9-13-44)76(118)96-56(31-45-17-20-52(103)21-18-45)79(121)101-67(84(126)127)82(124)102-68(85(4,5)6)83(125)98-60(69(88)111)38-128-35-47/h7-21,26-29,41-43,53-62,67-68,103H,22-25,30-40,86H2,1-6H3,(H2,87,104)(H2,88,111)(H,89,117)(H,90,122)(H,91,119)(H,92,123)(H,93,113)(H,94,115)(H,95,120)(H,96,118)(H,97,116)(H,98,125)(H,99,112)(H,100,114)(H,101,121)(H,102,124)(H,105,106)(H,107,108)(H,109,110)(H,126,127)/t41-,42+,43+,53-,54-,55-,56-,57-,58-,59-,60+,61+,62+,67?,68+/m0/s1
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| InChIKey |
SSNICADVCSVWJB-FZWCCHQESA-N
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| Pharmaceutical Properties |
Molecule Weight
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1863.086
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Polar area
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689.03
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Complexity
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1861.678615
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xlogp Value
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-3.1298
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Heavy Count
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130
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Rot Bonds
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20
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Hbond acc
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25
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Hbond Donor
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22
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The Activity Data of This Peptide
| Peptide Activity Information 1 | [1] | |||||
| KD | 3 nM | |||||
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Each Peptide-drug Conjugate Related to This Peptide
Full Information of The Activity Data of The PDC(s) Related to This Peptide
BT1718 [Phase 2]
Identified from the Human Clinical Data
| Experiment 1 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Grade 3 increased GGT |
8.30%
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| Patients Enrolled |
24 patients with various types of solid tumors.
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| Administration Dosage | 9.6 mg/m2 BIW | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
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| Description |
24 patients were enrolled with various types of solid tumors across both dose escalation cohorts (see table). BIW RP2D was determined as 7.2 mg/m2. The 2 patients with DLTs at 9.6 mg/m2 BIW experienced grade 3 increased GGT or fatigue. QW dose escalation continues at 20 mg/m2. Mean number of cycles received = 2.3 months (N = 24), with no objective responses observed to date in this unselected population.
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| Experiment 2 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Fatigue |
8.30%
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| Patients Enrolled |
24 patients with various types of solid tumors.
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| Administration Dosage | 9.6 mg/m2 BIW | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
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| Description |
24 patients were enrolled with various types of solid tumors across both dose escalation cohorts (see table). BIW RP2D was determined as 7.2 mg/m2. The 2 patients with DLTs at 9.6 mg/m2 BIW experienced grade 3 increased GGT or fatigue. QW dose escalation continues at 20 mg/m2. Mean number of cycles received = 2.3 months (N = 24), with no objective responses observed to date in this unselected population.
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Discovered Using Cell Line-derived Xenograft Model
| Experiment 1 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
12.50%
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| Administration Time | Twice a week for 12 days | ||||
| Administration Dosage | 1 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
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| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 72 days.
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| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
12.70%
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| Administration Time | Three times a week for 12 days | ||||
| Administration Dosage | 1 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
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| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 75 days.
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| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
18%
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| Administration Time | 14 days | ||||
| Administration Dosage | 1 mg/kg qw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
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| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
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| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
27%
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| Administration Time | 14 days | ||||
| Administration Dosage | 1 mg/kg biw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
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| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
85.40%
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| Administration Time | Three times a week for 12 days | ||||
| Administration Dosage | 3 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 74 days.
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| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 6 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
88%
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| Administration Time | 14 days | ||||
| Administration Dosage | 3 mg/kg qw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
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| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 7 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Lung squamous cell carcinoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
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| Administration Time | 14 days | ||||
| Administration Dosage | 10mg/kg | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
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| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive EBC-1 cells. | ||||
| In Vitro Model | Lung squamous cell carcinoma | EBC-1 cell | CVCL_2891 | ||
| Experiment 8 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
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| Administration Time | 14 days | ||||
| Administration Dosage | 10 mg/kg biw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
||||
| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 9 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
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| Administration Time | 14 days | ||||
| Administration Dosage | 3 mg/kg biw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
||||
| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 10 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Fibrosarcoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
|
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| Administration Time | 14 days | ||||
| Administration Dosage | 10 mg/kg qw | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
Click to Show/Hide
|
||||
| In Vivo Model | Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells. | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 11 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
|
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| Administration Time | 12 days | ||||
| Administration Dosage | 10 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Treatment with BDCs containing the most labile linkers (BT17BDC17 orBT1718) showed rapid and complete tumour clearance (EBC-1 cells).
|
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| In Vivo Model | Mice implanted with MT1-positive EBC-1 cells | ||||
| In Vitro Model | Lung squamous cell carcinoma | EBC-1 cell | CVCL_2891 | ||
| Experiment 12 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
|
|||
| Administration Time | Twice a week for 12 days | ||||
| Administration Dosage | 10 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
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| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days.
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| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 13 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
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| Administration Time | Twice a week for 12 days | ||||
| Administration Dosage | 3 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 71 days.
|
||||
| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
| Experiment 14 Reporting the Activity Data of This PDC | [3] | ||||
| Indication | Solid tumor | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
100%
|
|||
| Administration Time | Three times a week for 12 days | ||||
| Administration Dosage | 10 mg/kg | ||||
| Evaluation Method | Tumor volume detection | ||||
| MOA of PDC |
BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue.
Click to Show/Hide
|
||||
| Description |
Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 73 days.
|
||||
| In Vivo Model | Mice implanted with MT1-positive HT-1080 cells | ||||
| In Vitro Model | Fibrosarcoma | HT-1080 cell | CVCL_0317 | ||
References