Peptide Information
General Information of This Peptide
| Peptide ID |
PEP00179
|
|||||
|---|---|---|---|---|---|---|
| Peptide Name |
DPI-4452
|
|||||
| Structure |
|
|||||
| Peptide Type |
Cyclic
|
|||||
| Peptide Half Life Period |
0.28 h
|
|||||
| PDC Transmembrane Types | Cell targeting peptides (CTPs) | |||||
| Distribution |
DPI-4452 biodistribution was evaluated in male and female beagle dogs. Each animal received a single dose of 200 MBq of [68Ga]Ga-DPI-4452 followed, 14 d later, by a single dose of 1,000 MBq of [177Lu]Lu-DPI-4452. Organ uptake of radioactivity over time was determined using PET/CT imaging and SPECT/CT imaging, respectively. At early time points, significant uptake occurred in the bladder, likely due to renal elimination. The highest sustained uptake was seen in the stomach and small intestine (Fig. 4), consistent with CAIX expression in these organs (1,2,5,18). No or low uptake was seen in the rest of the body, namely, the kidneys, bone marrow, blood, heart wall, and skin (Fig. 5; Supplemental Fig. 16).
|
|||||
| Excretion |
In a pharmacokinetic study after a single intravenous dose of 0.1 mg/kg in beagle dogs, the plasma half-life of DPI-4452 was 0.38 h, denoting rapid elimination of the peptide from the systemic circulation (Table 4).
|
|||||
| Formula |
C70H96N16O21S3
|
|||||
| Isosmiles |
CC(C)C[C@@H]1NC(=O)[C@H](Cc2cccc(NC(=O)CCCS(N)(=O)=O)c2)NC(=O)C(CC(=O)O)NC(=O)[C@H]2CCCN2C(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(N)=O)CSCc2cccc(c2)CSC[C@H](C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@@H]([C@@H](C)O)NC1=O
|
|||||
| InChI |
InChI=1S/C70H96N16O21S3/c1-36(2)24-47-65(100)85-59(37(3)88)69(104)81-49(28-41-30-75-45-15-5-4-14-43(41)45)63(98)82-51(31-87)66(101)83-52(60(73)95)34-108-32-39-11-6-12-40(25-39)33-109-35-53(84-61(96)44(71)18-20-55(72)89)67(102)77-46(19-21-57(91)92)70(105)86-22-8-16-54(86)68(103)80-50(29-58(93)94)64(99)79-48(62(97)78-47)27-38-10-7-13-42(26-38)76-56(90)17-9-23-110(74,106)107/h4-7,10-15,25-26,30,36-37,44,46-54,59,75,87-88H,8-9,16-24,27-29,31-35,71H2,1-3H3,(H2,72,89)(H2,73,95)(H,76,90)(H,77,102)(H,78,97)(H,79,99)(H,80,103)(H,81,104)(H,82,98)(H,83,101)(H,84,96)(H,85,100)(H,91,92)(H,93,94)(H2,74,106,107)/t37-,44+,46+,47+,48+,49+,50?,51+,52-,53+,54-,59-/m1/s1
|
|||||
| InChIKey |
OFRFBUOGJBOUFA-ICXOQSAKSA-N
|
|||||
| Pharmaceutical Properties |
Molecule Weight
|
1593.83
|
Polar area
|
614.52
|
||
|
Complexity
|
1592.609807
|
xlogp Value
|
-3.6685
|
|||
|
Heavy Count
|
110
|
Rot Bonds
|
24
|
|||
|
Hbond acc
|
22
|
Hbond Donor
|
19
|
|||
The Activity Data of This Peptide
| Peptide Activity Information 1 | [1] | |||||
| KD | 0.25 nM | |||||
|---|---|---|---|---|---|---|
| Binding Affinity Assay |
Recombinant CA proteins (Sino Biologic) were immobilized on Biacore CM5 sensor chips or biotin CAPture chips (Biacore). DPI-4452 binding was measured using the Biacore Liquid System (Biacore), and binding kinetic parameters were calculated.
|
|||||
| Experimental Condition | Biacore CM5 sensor chips in vitro | |||||
| Peptide Activity Information 2 | [1] | |||||
| Dissociation half-life | 99 min | |||||
| Binding Affinity Assay |
Recombinant CA proteins (Sino Biologic) were immobilized on Biacore CM5 sensor chips or biotin CAPture chips (Biacore). DPI-4452 binding was measured using the Biacore Liquid System (Biacore), and binding kinetic parameters were calculated.
|
|||||
| Experimental Condition | Biacore CM5 sensor chips in vitro | |||||
Each Peptide-drug Conjugate Related to This Peptide
Full Information of The Activity Data of The PDC(s) Related to This Peptide
[177Lu]Lu-DPI-4452 [Phase 1/2]
Discovered Using Cell Line-derived Xenograft Model
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Colon adenocarcinoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
29.40%
|
|||
| Administration Time | 23 days | ||||
| Administration Dosage | 33 MBq, single dose | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice HT-29 CRC cells xenograft models. | ||||
| In Vitro Model | Colon cancer | HT29 cell | CVCL_A8EZ | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Renal cancer | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
73.30%
|
|||
| Administration Time | 15 days | ||||
| Administration Dosage | 100 MBq, single dose | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models. | ||||
| In Vitro Model | Renal cell carcinoma | SK-RC-52 cell | CVCL_6198 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Renal cancer | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
77.80%
|
|||
| Administration Time | 15 days | ||||
| Administration Dosage | 33 MBq, single dose | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models. | ||||
| In Vitro Model | Renal cell carcinoma | SK-RC-52 cell | CVCL_6198 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Colon adenocarcinoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
82.40%
|
|||
| Administration Time | 23 days | ||||
| Administration Dosage | 100 MBq, single dose | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice HT-29 CRC cells xenograft models. | ||||
| In Vitro Model | Colon cancer | HT29 cell | CVCL_A8EZ | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Colon adenocarcinoma | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
82.40%
|
|||
| Administration Time | 23 days | ||||
| Administration Dosage | 33 MBq, QW3 | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice HT-29 CRC cells xenograft models. | ||||
| In Vitro Model | Colon cancer | HT29 cell | CVCL_A8EZ | ||
| Experiment 6 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Renal cancer | ||||
| Efficacy Data | Tumor Growth Inhibition value (TGI) |
84.40%
|
|||
| Administration Time | 15 days | ||||
| Administration Dosage | 33 MBq, QW3 | ||||
| MOA of PDC |
Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1α expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1α leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy.
Click to Show/Hide
|
||||
| Description |
The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial.
Click to Show/Hide
|
||||
| In Vivo Model | Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models. | ||||
| In Vitro Model | Renal cell carcinoma | SK-RC-52 cell | CVCL_6198 | ||
Debio-0328 [Phase 1]
Identified from the Human Clinical Data
| Experiment 1 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV mean values |
39
|
|||
| Patients Enrolled |
48 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 2 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV mean values |
62
|
|||
| Patients Enrolled |
51 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 3 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV mean values |
89
|
|||
| Patients Enrolled |
54 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 4 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV max values |
106
|
|||
| Patients Enrolled |
51 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 5 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV max values |
109
|
|||
| Patients Enrolled |
48 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 6 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | SUV max values |
212
|
|||
| Patients Enrolled |
54 years old patient with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively.
Click to Show/Hide
|
||||
| Experiment 7 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | Headache |
33.30%
|
|||
| Patients Enrolled |
3 patients with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
No clinically significant toxicity was observed; treatment-emergent adverse events (headache and increased blood creatine kinase [1 each; 33.3%]) were not causally related to [68Ga]Ga-DPI-4452. No significant changes in vital signs, laboratory assessments, or electrocardiograms were observed.
|
||||
| Experiment 8 Reporting the Activity Data of This PDC | [2] | ||||
| Indication | Clear cell renal cell carcinoma | ||||
| Efficacy Data | Blood creatine kinase increase |
33.30%
|
|||
| Patients Enrolled |
3 patients with metastatic ccRCC.
|
||||
| Administration Dosage | 185 MBq (±20%) | ||||
| MOA of PDC |
Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC.
Click to Show/Hide
|
||||
| Description |
No clinically significant toxicity was observed; treatment-emergent adverse events (headache and increased blood creatine kinase [1 each; 33.3%]) were not causally related to [68Ga]Ga-DPI-4452. No significant changes in vital signs, laboratory assessments, or electrocardiograms were observed.
|
||||
References