Linker Information
General Information of This Linker
| Linker ID |
LIN0PWYIO
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| Linker Name |
DOTA-P-toluene isothiocyanate
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| Linker Type |
Chelating agent
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| Antibody-Linker Relation |
Uncleavable
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| Structure |
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| Formula |
C24H33N5O8S
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| Isosmiles |
O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(Cc2ccc(N=C=S)cc2)CN(CC(=O)O)CC1
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| InChI |
InChI=1S/C24H33N5O8S/c30-21(31)13-26-5-6-27(14-22(32)33)9-10-29(16-24(36)37)20(12-28(8-7-26)15-23(34)35)11-18-1-3-19(4-2-18)25-17-38/h1-4,20H,5-16H2,(H,30,31)(H,32,33)(H,34,35)(H,36,37)
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| InChIKey |
UDOPJKHABYSVIX-UHFFFAOYSA-N
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| Pharmaceutical Properties |
Molecule Weight
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551.622
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Polar area
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174.52
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Complexity
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38
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xlogp Value
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-0.108
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Heavy Count
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38
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Rot Bonds
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11
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Hbond acc
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10
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Hbond Donor
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4
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Each Antibody-drug Conjugate Related to This Linker
Full Information of The Activity Data of The ADC(s) Related to This Linker
Lintuzumab Ac-225 [Phase 1 (discontinued)]
Identified from the Human Clinical Data
| Experiment 1 Reporting the Activity Date of This ADC | [1] | ||||
| Related Clinical Trial | |||||
| NCT Number | NCT06802523 | Clinical Status | PHASE1 | ||
| Clinical Description |
A Phase I Study of Lintuzumab-Ac-225 in Combination With Venetoclax and ASTX-727 in Adults With Newly Diagnosed AML
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| Experiment 2 Reporting the Activity Date of This ADC | [2] | ||||
| Patients Enrolled |
Inclusion criteria: Phase I - untreated AML (including secondary/prior MDS) patients ≥60 years (or ≥70) unfit for intensive chemo, with ≥20% blasts (>25% CD33+), adequate organ function, ECOG≤3; Phase II - similar diagnosis with additional cardio-pulmonary-hepatic-renal comorbidity specifications, circulating blasts <200/mm <sup>3</sup> (hydroxyurea allowed), stricter organ function thresholds (Cr<2.0 mg/dL, CrCl≥50 mL/min, bilirubin≤2.0 mg/dL, AST/ALT<5×ULN), and ECOG≤2.
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| Administration Dosage |
Cytarabine + Lintuzumab-Ac225 Cytarabine days 1 to 10 of each cycle. Doses were divided into 2 equal fractions with the first fraction given approx. 4-7 days after 1 cycle of low dose cytarabine and the second fraction given 4-7 days after the first fraction, followed by up to 11 more cycles. Furosemide (Phase 1 only) and Spironolactone were administered after Lintuzumab-Ac225.
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| Related Clinical Trial | |||||
| NCT Number | NCT02575963 | Clinical Status | PHASE1|||PHASE2 | ||
| Clinical Description |
A Phase I/II Study of Lintuzumab-Ac225 in Older Patients With Untreated Acute Myeloid Leukemia
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| Primary Endpoint |
Phase I primary endpoint: MTD determination of Lintuzumab-Ac225 [Cycle 1, up to 52 days] with DLT evaluation in cohorts (MTD exceeded if ≥2/3-6 patients experience DLT). Phase II primary endpoint: composite complete response rate (CR+CRp+CRi) [First evaluation at 42 days post-treatment] to assess antileukemic activity.
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| Other Endpoint |
Phase II secondary endpoints: PFS, LFS, and OS [all at 1 year], along with toxicity spectrum evaluation for safety assessment [1 year].
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| Experiment 3 Reporting the Activity Date of This ADC | [3] | ||||
| Patients Enrolled |
Key inclusion: Age≥18 with relapsed/refractory AML (primary/secondary/t-AML) or MDS-progressed AML, ECOG 0-2, >25% CD33+ blasts, bilirubin≤2xULN, AST/ALT≤5xULN, CrCl≥50mL/min, LVEF>40%, with contraception requirements.
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| Administration Dosage |
Lintuzumab Ac225 (Dose 1 - 0.25 uCi/kg Ac-225 with 1.6 ug/kg lintuzumab)
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| Related Clinical Trial | |||||
| NCT Number | NCT03441048 | Clinical Status | PHASE1 | ||
| Clinical Description |
A Phase I Study of Lintuzumab-Ac225 in Combination with CLAG-M Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia
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| Primary Endpoint |
Primary endpoints include DLT assessment [28 days] using a 3+3 dose-escalation design (0.25-1.25 uCi/kg) with MTD defined as the highest dose where ≤1/6 subjects experience DLT, SAE monitoring per CTCAE v4.03 [60 days], and 2-year OS.
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| Other Endpoint |
Secondary efficacy endpoints: CR (BM blasts <5% with ANC≥1000/uL & platelets≥100k/uL), CRi (CR without count recovery), MLFS (blasts <5% without count recovery), PR (≥50% blast reduction to <25% with normalized counts) [all up to Day 60], and 1-year PFS.
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| Experiment 4 Reporting the Activity Date of This ADC | [4] | ||||
| Patients Enrolled |
Key inclusion: R/R AML (primary/secondary/ts-AML) with ≥1 prior treatment failure or relapse (≥5% BM blasts), circulating blasts ≤200/uL (hydroxyurea permitted), ECOG≤2, CrCl≥50mL/min, AST/ALT≤3xULN, bilirubin≤3xULN.
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| Administration Dosage |
Lintuzumab-Ac225 administered on Day 5 of each cycle for four cycles (unless in the 0.5 uCi/kg or 0.25 uCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review).
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| Related Clinical Trial | |||||
| NCT Number | NCT03867682 | Clinical Status | PHASE1|||PHASE2 | ||
| Clinical Description |
A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
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| Primary Endpoint |
Primary objectives include MTD determination of Lintuzumab-Ac225 combined with venetoclax in R/R AML (CD33+) [Cycle 1, up to 48 days] and assessment of overall response rate (CR+CRh+CRi) [6 months].
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| Other Endpoint |
Secondary endpoints: ORR (CR/CRh/CRi), OS/DFS at 6/12/24 months, AE/SAE incidence [2 years], BH3 priming assay results [Cycle 1], MRD negativity rate [from first dose], and Grade 3/4 lab abnormalities [2 years].
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| Experiment 5 Reporting the Activity Date of This ADC | [5] | ||||
| Patients Enrolled |
Key inclusion: Histologically confirmed R/R AML (primary/secondary/ts-AML) with ≥1 prior treatment failure or relapse (≥5% BM blasts), WBC<10×10<sup>9</sup>/L (hydroxyurea permitted), age>18, CrCl≥50mL/min, AST/ALT≤3xULN, bilirubin≤3xULN, ECOG≤2.
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| Administration Dosage |
Lintuzumab-Ac225 will be administered on Day 8 of each cycle for four cycles (unless in the 0.5 uCi/kg or 0.25 uCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review).
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| Related Clinical Trial | |||||
| NCT Number | NCT03932318 | Clinical Status | PHASE1|||PHASE2 | ||
| Clinical Description |
A Phase I/II Study of Venetoclax and Azacitidine and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
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| Primary Endpoint |
Primary objectives include determining the MTD of Lintuzumab-Ac225 in combination with venetoclax/azacitidine for CD33+ AML [Cycle 1, up to 48 days] and assessing overall response rate (CR+CRh+CRi+MLFS) [6 months].
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| Other Endpoint |
Secondary endpoints: ORR (CR/CRh/CRi/MLFS), OS at 6/12/24 months (Phase I/II), DFS [2 years], AE/SAE incidence [2 years], Grade 3/4 lab abnormalities [2 years], BH3 priming assay results [Cycle 1], and MRD negativity rate [from first dose].
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| Experiment 6 Reporting the Activity Date of This ADC | [6] | ||||
| Patients Enrolled |
Key inclusion: Confirmed relapsed/refractory multiple myeloma (≥3 prior regimens) with measurable disease (serum M-protein ≥0.5g/dL IgG/IgA or urinary light chain ≥200mg/24h), CD33+ expression in >25% myeloma cells, resolved toxicities (Grade ≤2), normal electrolytes, adequate organ function, and ECOG ≤2.
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| Administration Dosage |
Starting dose - 0.5 uCi/Kg IV infusion of Lintuzumab AC225 on Day 1 of each cycle with dose escalation 1 uCi/Kg and 1.5 uCi/Kg or de-escalation to 0.25 uCi/Kg.
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| Related Clinical Trial | |||||
| NCT Number | NCT02998047 | Clinical Status | PHASE1 | ||
| Clinical Description |
A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma
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| Primary Endpoint |
Primary objectives include establishing the MTD of Lintuzumab-AC225 monotherapy [average 2.5 years] and evaluating treatment-emergent adverse events for safety assessment [average 2.5 years].
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| Other Endpoint |
Secondary endpoints: Comprehensive response evaluation (ORR, CR, sCR, VGPR, PR), PFS, and OS [all average 2.5 years], with efficacy assessments including serum/urine paraprotein levels and bone marrow analyses.
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| Experiment 7 Reporting the Activity Date of This ADC | [7] | ||||
| Efficacy Data | Objective Response Rate (ORR) |
67%
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| Patients Enrolled |
Patients with more than 25% of leukemic blasts must have been CD33 positive by flow cytometry.
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| Administration Dosage |
Induction consisted of G-CSF, 300 mg/d, given D1-6, cladribine 5 mg/m2, given D2-6, cytarabine 2 ug/m2, given D2-6, and mitoxantrone 10 mg/m2, given D2-4. Lintuzumab Ac225 was administered as a single dose on either day 7, 8, or 9 with a dose of 0.25 uCi/kg, 0.50 uCi/kg, or 0.75 uCi/kg.
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| Related Clinical Trial | |||||
| NCT Number | NCT03441048 | Clinical Status | Phase 1 | ||
| Clinical Description |
A phase 1 study of lintuzumab-Ac225 in combination with CLAG-M chemotherapy in patients with relapsed/refractory acute myeloid leukemia.
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| Experiment 8 Reporting the Activity Date of This ADC | [8] | ||||
| Related Clinical Trial | |||||
| NCT Number | NCT02575963 | Clinical Status | Phase 1 | ||
| Clinical Description |
A phase 1/2 study of lintuzumab-Ac225 in older patients with untreated acute myeloid leukemia.
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| Experiment 9 Reporting the Activity Date of This ADC | [9] | ||||
| Related Clinical Trial | |||||
| NCT Number | NCT03932318 | Clinical Status | Phase 1 | ||
| Clinical Description |
A phase 1/2 study of venetoclax and azacitidine and lintuzumab-Ac225 in patients with refractory or relapsed AML.
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| Experiment 10 Reporting the Activity Date of This ADC | [10] | ||||
| Related Clinical Trial | |||||
| NCT Number | NCT03867682 | Clinical Status | Phase 1 | ||
| Clinical Description |
A phase 1/2 study of venetoclax and lintuzumab-Ac225 in patients with refractory or relapsed AML.
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| Experiment 11 Reporting the Activity Date of This ADC | [11] | ||||
| Related Clinical Trial | |||||
| NCT Number | NCT02998047 | Clinical Status | Phase 1 | ||
| Clinical Description |
A phase 1 study of lintuzumab-Ac225 in patients with refractory multiple myeloma.
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References