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| Targets |
The primary target is DLL3, a cell‑surface protein that inhibits Notch signalling and is highly upregulated in about 80% of SCLC tumours. DLL3 is a tumour‑associated antigen that is internalised upon antibody binding, making it suitable for both immune engagement and potentially antibody‑drug conjugates. The anti‑DLL3 arm binds to the extracellular domain of DLL3 with high affinity (KD ≈ 0.5–2 nM), and its specificity ensures that T‑cell engagement occurs preferentially at the tumour site. There is no cross‑reactivity with other Notch ligands (DLL1, DLL4, JAG1, JAG2).
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| ln Vitro |
In vitro, the anti‑DLL3 antibody fragment demonstrates potent and specific binding to DLL3‑positive cell lines, including SCLC lines (e.g., NCI‑H82, NCI‑H526) and neuroblastoma cells. Binding affinity is measured by flow cytometry and SPR, with EC₅₀ values for cell binding in the low nanomolar range. When incorporated into the BiTE format, the anti‑DLL3 arm enables T‑cell‑dependent cellular cytotoxicity (TDCC) against target cells, with EC₅₀ values typically between 10–100 pM. The antibody fragment does not bind to DLL3‑negative cells, confirming specificity. It also facilitates target‑mediated internalisation, which is useful for payload delivery.
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| ln Vivo |
In vivo, the anti‑DLL3‑containing BiTE (AMG‑757) has been evaluated in mouse xenograft models of SCLC. Administration at doses of 0.1–1 mg/kg (IV) results in complete tumour regression in established NCI‑H82 tumours. The antibody fragment itself, when not in BiTE format, may also exert modest anti‑tumour effects via antibody‑dependent cellular cytotoxicity (ADCC) in the presence of effector cells. In cynomolgus monkeys, the DLL3‑targeting BiTE shows a manageable safety profile with transient cytokine release at higher doses, but no off‑target toxicity due to the restricted expression of DLL3.
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| Enzyme Assay |
Non‑cell binding assays include SPR to measure the affinity of the anti‑DLL3 Fab fragment to recombinant human DLL3 extracellular domain (ECD). The ECD is immobilised on a CM5 sensor chip, and increasing concentrations of the antibody (0.1–100 nM) are flowed over the chip. Association and dissociation rates (ka, kd) are recorded, and the KD is calculated using a 1:1 Langmuir binding model. ELISA is also used: DLL3‑ECD is coated onto plates (1 µg/mL), blocked with BSA, and the antibody is added at serial dilutions, followed by HRP‑conjugated anti‑human IgG detection. The binding EC₅₀ is determined from the absorbance curves.
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| Cell Assay |
In vitro cellular binding assays use flow cytometry with DLL3‑positive NCI‑H82 cells and DLL3‑negative HEK293 cells as controls. Cells are incubated with the anti‑DLL3 antibody at concentrations of 0.001–100 µg/mL for 30 min on ice, washed, and stained with a fluorescently labelled secondary antibody. Mean fluorescence intensity is measured, and EC₅₀ is calculated. For TDCC assays, target cells are labelled with a fluorescent viability dye and co‑cultured with human PBMCs (effector:target ratio 10:1) in the presence of serial dilutions of the antibody (or the BiTE) for 24–48 h. Specific lysis is quantified by flow cytometry, and EC₅₀ values are derived.
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| Animal Protocol |
In vivo efficacy studies are performed using immunodeficient NOD/SCID or NSG mice bearing subcutaneous SCLC xenografts. The anti‑DLL3 antibody (or the BiTE molecule containing it) is administered intravenously at doses of 0.1–3 mg/kg, typically every 3‑4 days for 2‑3 weeks. Tumour volumes are measured with callipers twice weekly. Blood samples are collected for PK assessment and to measure T‑cell activation markers (CD69, CD25) and cytokines (IFN‑γ, TNF‑α). At termination, tumours are excised for immunohistochemical analysis of DLL3 expression and immune infiltrate.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in cynomolgus monkeys show that the half‑life of the anti‑DLL3 Fab fragment in BiTE format (with an Fc domain) is approximately 3–5 days, while the standalone Fab fragment has a shorter half‑life (~8‑12 h). The volume of distribution is consistent with the vascular space, and clearance is moderate (~10‑15 mL/kg/h). The antibody fragment undergoes proteolytic degradation and is cleared via the reticuloendothelial system. In humans, the half‑life is projected to be around 5‑7 days, supporting weekly or bi‑weekly dosing. No accumulation is observed with repeated dosing.
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| Toxicity/Toxicokinetics |
Toxicology studies in cynomolgus monkeys have evaluated the anti‑DLL3‑based BiTE at doses up to 10 mg/kg weekly for 4 weeks. Adverse effects are primarily related to cytokine release syndrome (CRS) at the highest doses (≥3 mg/kg), manifesting as transient fever, hypotension, and elevated IL‑6. These effects are manageable with pre‑medication. No specific organ toxicity or haematological toxicity is noted at therapeutic doses. The NOAEL is established at 1 mg/kg. No immunogenicity is observed, as the antibody is fully humanised. This safety profile supports clinical development.
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| References | |
| Additional Infomation |
Additional information: This anti‑DLL3 antibody is the targeting component of AMG‑757 (tarlatamab), a BiTE that has received Breakthrough Therapy designation and FDA approval for extensive‑stage small‑cell lung cancer (ES‑SCLC). The antibody arm is critical for tumour targeting, while the other arm engages CD3 on T cells. The antibody is produced in CHO cells with high purity and stability. It is not available as a standalone drug but is the active targeting moiety in approved and investigational bispecific agents. Ongoing trials are evaluating DLL3‑targeting agents in other neuroendocrine tumours. The antibody has been extensively characterised, and its crystal structure has been resolved, providing insights into its high specificity.
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| Appearance |
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) |
Typically soluble in DMSO (e.g. 10 mM)
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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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