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| 5mg |
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| Targets |
Izeltabart targets ADAM9, a transmembrane protein that is a member of the ADAM family of metalloproteases. ADAM9 is highly expressed in a variety of solid tumors, including lung, breast, pancreatic, and gastric cancers, with limited expression in normal adult tissues, making it an attractive target for ADC therapy. The antibody component binds specifically to ADAM9 on the cell surface. Upon binding, the ADC is internalized, and the maytansinoid payload is released intracellularly. The payload, a potent microtubule-disrupting agent, targets the tubulin cytoskeleton, inhibiting cell division and leading to cell death.
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| ln Vitro |
In vitro, Izeltabart (IMGC-936) has been shown to exhibit potent cytotoxicity against a panel of ADAM9-positive human tumor cell lines. The ADC is internalized by target cells, and the maytansinoid payload binds to tubulin, inhibiting microtubule assembly and disrupting the mitotic spindle. This results in G2/M cell cycle arrest and subsequent apoptosis. Cytotoxicity is specific to ADAM9-expressing cells, as the ADC shows minimal activity in ADAM9-negative cells. The IC₅0 values are typically in the nanomolar to picomolar range, depending on the level of ADAM9 expression on the target cells. Competition assays with an excess of unconjugated antibody block the ADC's activity, confirming target-specific killing.
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| ln Vivo |
In vivo, Izeltabart (IMGC-936) has demonstrated potent antitumor activity in multiple xenograft models of human cancer. In studies using mice bearing ADAM9-positive tumors (e.g., lung, pancreatic), a single dose or multiple doses of the ADC (e.g., 5-10 mg/kg, IV) led to significant tumor growth inhibition (TGI) and, in some cases, complete tumor regression. The activity was dose-dependent and well-correlated with ADAM9 expression levels. In patient-derived xenograft (PDX) models, which more closely recapitulate human tumor heterogeneity, IMGC-936 also showed robust efficacy. These in vivo studies confirm the potential of this ADC as a targeted therapy for ADAM9-driven cancers.
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| Enzyme Assay |
A typical non-cellular binding assay for Izeltabart involves surface plasmon resonance (SPR) to measure the binding affinity of the antibody to recombinant ADAM9 protein. The recombinant human ADAM9 is immobilized on a sensor chip. Izeltabart is injected at various concentrations (0.1-100 nM) over the surface, and the association (ka) and dissociation (kd) rate constants are determined. The equilibrium dissociation constant (KD) is calculated, which is typically in the low nanomolar range, indicating high affinity. For the maytansinoid payload, a tubulin polymerization assay is performed: tubulin is incubated with the payload in a buffer containing GTP, and the increase in fluorescence (due to microtubule formation) is measured at 37degC. The IC₅0 for the inhibition of tubulin assembly is calculated.
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| Cell Assay |
A typical in vitro cell-based assay for Izeltabart uses a panel of human cancer cell lines with varying levels of ADAM9 expression. Cells are seeded in 96-well plates and treated with serial dilutions of the ADC (0.001-100 nM) for 96 hours. Cell viability is measured using the CellTiter-Glo luminescent assay to calculate the IC₅0. An internalization assay is also performed using flow cytometry. Cells are incubated with the ADC on ice to allow binding, then shifted to 37degC. At intervals (0, 30, 60, 120 min), cells are washed to remove surface-bound antibodies, and a fluorescently labeled secondary antibody is used to detect residual surface signal. The decrease in surface signal over time indicates internalization.
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| Animal Protocol |
In vivo animal studies for Izeltabart are conducted in female BALB/c nude mice (6-8 weeks old) bearing subcutaneous xenografts of ADAM9-positive cell lines (e.g., NCI-H1975 lung cancer or BxPC-3 pancreatic cancer). Once tumors reach a volume of 100-200 mm3, mice are randomized into groups (n=8-10). Izeltabart is administered intravenously at doses ranging from 1 to 30 mg/kg, once weekly for three doses. Tumor volumes are measured twice weekly with calipers. Body weight is also monitored as a safety indicator. At study termination, tumors are excised for ex vivo analysis, including IHC for Ki-67 (proliferation marker) and TUNEL (apoptosis marker), as well as LC-MS/MS to quantify the payload concentration.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of Izeltabart (IMGC-936) are characteristic of an ADC. In preclinical species (e.g., cynomolgus monkeys), the ADC exhibits a long terminal half-life (t1/2) of approximately 5-10 days. The clearance (CL) is low (e.g., <10 mL/day/kg), and the volume of distribution (Vd) is low, consistent with the antibody mainly distributing in the vascular and extracellular spaces. The ADC is stable in circulation, with a low rate of deconjugation (less than 10% payload release after 21 days). The primary route of elimination is proteolytic degradation of the antibody component. The released maytansinoid payload is rapidly cleared and metabolized.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies are essential to characterize the safety profile and determine the maximum tolerated dose (MTD). The primary toxicities observed in non-human primates are typically on-target effects (related to ADAM9 expression in normal tissues, such as the eye, liver, and skin) and off-target effects from the payload, which may include bone marrow suppression and gastrointestinal toxicity. However, IMGC-936 was designed with a stable linker to minimize premature payload release and reduce systemic toxicity. The MTD was established through dose-escalation studies, and the toxicokinetic profile was correlated with systemic exposure (AUC). No human toxicity data is available as the drug is investigational.
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| References | |
| Additional Infomation |
Izeltabart (IMGC-936) is an investigational drug that is not yet approved for clinical use. It has completed preclinical evaluation and has been studied in Phase 1 clinical trials for patients with ADAM9-expressing advanced solid tumors. The mechanism of action involves specific binding to ADAM9 on cancer cells, followed by internalization and intracellular release of a maytansinoid payload, which inhibits microtubule polymerization and causes cell cycle arrest and cell death. The clinical trial status of IMGC-936 can be verified on clinicaltrials.gov. For research use only; not for human therapeutic administration outside of approved clinical trials.
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| CAS # |
2642078-60-0
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| Appearance |
Colorless to light yellow liquid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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