NN3201
Based on 1 Customer Validation
NN3201 is a c-Kit-targeting antibody-drug conjugate (ADC) with high affinity (KD = 0.19 pM). NN3201 is composed of 4-(3-Tosyl-2-(tosylmethyl)propanoyl)benzoic acid-glu(PEG24-Me)-val-cit-NH-benzyloxyformic acid-MMAE (HY-178219) and an anti-c-Kit human monoclonal antibody NN2101 (HY-P991293). NN3201 rapidly internalizes and inhibits stem cell factor (SCF)-driven signaling, thereby delivering its payload to induce cell cycle arrest and apoptosis. NN3201 exhibits no Fc-mediated effector functions antibody-dependent cell-mediated cytotoxicity (ADCC)/complement-dependent cytotoxicity (CDC) due to reduced FcγR binding. NN3201 exhibits significant c-Kit-dependent anti-tumor efficacies in various tumor models. NN3201 can be used in small cell lung cancer (SCLC) and gastrointestinal stromal tumor (GIST) and acute myeloid leukemia (AML) research[1][2].
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Actividad biológica
NN3201 (1 µg/mL, 1 h) exhibits dose-dependent binding to c-Kit-high and c-Kit-medium cell lines, which saturated at 315 pM, with no binding observed to c-Kit-low or negative cell lines[1].
NN3201 (1 µg/mL, 0.5-24 h) internalizes rapidly (within 30 minutes) and continuously in c-Kit-positive GIST-T1 cells, with the signal increasing for up to 24 hours, but its internalization was c-Kit-dependent[1].
NN3201 (3-7 days) demonstrates potent, c-Kit-dependent cytotoxicity mediated by its MMAE payload in a panel of positive cell lines, with GI50 values of 0.09 nM (GIST-T1), 0.69 nM (GIST-430), 0.12 nM (GIST-430/654), and 17.06 nM (NCI-H1048)[1].
NN3201 (0.01-1 µg/mL, 1 h) dose-dependently decreases the SCF-mediated phosphorylation on c-Kit (Y719, Y568/570), Erk1/2, and Akt (S473) in NCI-H1048 cells, while only partially suppressing phosphorylation (pY568/570 c-Kit and pErk1/2) in GIST-430/654 cells[1].
NN3201 (1 µg/mL, 1-3 days) induces c-Kit degradation and signaling inhibition through continuous internalization, which triggered apoptosis, demonstrated by the increase in cleaved caspase-3 and caspase-7[1].
NN3201 (5 µg/mL, 24-48 h) induces cell cycle arrest in the G2/M and sub-G1 phases, which is attributed to the microtubule-disrupting action of its released MMAE payload[1].
NN3201 (4 µg/mL, 7 days) triggers a potent bystander effect, mediated by free MMAE released from NN3201-treated GIST-430/654 cells, which killed neighboring MCF7-GFP⁺ cancer cells with negligible c-Kit expression[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MCF7-GFP+ cells
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Concentration:4 μg/mL
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Incubation Time:7 days
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Result:Exhibited negligible cytotoxicity (GI50 >20 µg/mL) against the c-Kit-negative MCF7-GFP⁺ cell line, consistent with its target-dependent mechanism and in sharp contrast to the potent activity of its free payload, MMAE (GI50 = 4.96 nM).
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Cell Line:GIST-430/654 and NCI-H1048 cells
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Concentration:1 μg/mL
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Incubation Time:24 and 48 h
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Result:Induced substantial cell cycle arrest at the G2/M phase and increased the sub-G1 population in both cell lines.
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Cell Line:GIST-430/654 and MCI-H1048 cells
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Concentration:1 μg/mL
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Incubation Time:1, 2, and 3 days
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Result:Induced a time-dependent degradation of c-Kit in both cell lines.
Increased levels of cleaved caspase-3 and caspase-7.
Eventually inhibited the c-Kit downstream signaling pathway by sustained internalization and degradation of the NN3201-c-Kit complex over 3 days.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female C.B-17 SCID mice (5-6 weeks old) subcutaneously injected with GIST-T1 cells[1]
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Dosage:0.5, 1.5 and 3.0 mg/kg
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Administration:i.v., Q10D x 3
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Result:Completely regressed tumor volume for up to 112 days at 1.5 and 3 mg/kg, with Imatinib (HY-15463) (100 mg/kg, p.o., Q1D x 30) only inhibited tumor progression during the treatment period.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:NOG mice (5-6 weeks old) subcutaneously injected with GIST-430/654 cells[1]
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Dosage:1, 3 and 5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Induced significant tumor shrinkage at 3 mg/kg and 5 mg/kg, and stably controlled until day 42 and 49, respectively.
Induced tumor growth inhibition (TGI) of 47.2% on day 21 at 1 mg/kg, which was similar to that by 30 mg/kg of Sunitinib (HY-10255A) (30 mg/kg, p.o., Q1D x 21; TGI of 45.2% on day 21).
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female NOD/SCID mice subcutaneously implanted with GS5108 tumors[1]
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Dosage:3, 5 and 10 mg/kg
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Administration:i.v., Q1W x 3
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Result:Induced durable tumor stasis at 10 mg/kg, which was followed by significant tumor regression for up to 60 days.
Demonstrated superior in vivo efficacy over all standard-of-care (SoC) treatments in the 3rd line GIST models.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female C.B-17 SCID mice (5-6 weeks old) subcutaneously injected with NCI-H526 cells[1]
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Dosage:1, 1.5, 2, 2.5 and 3 mg/kg
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Administration:i.v., Q1W x 3
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Result:Induced complete regression of the tumor with no regrowth after 70 and 84 days at 2.5 and 3 mg/kg.
Exhibited 84.9% of TGI compared to the vehicle control on day 17 at 2 mg/kg.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female C.B-17 SCID mice (5-6 weeks old) subcutaneously injected with NCI-H1048 cells[1]
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Dosage:1, 3, and 5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Showed TGI of 95.1 % on day 21 at 1 mg/kg, better than the combination of Carboplatin (HY-17393) (60 mg/kg, i.p., day 0 and 10) and Etoposide (HY-13629) (3 mg/kg. i.p., day 0~4 and 10~14; TGI = 70.51% on day 21).
Induced complete tumor remission for up to 35 days and 56 days at 3 mg/kg and 5 mg/kg, respectively.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female C.B-17 SCID mice (5-6 weeks old) subcutaneously injected with NCI-H1048 cells[1]
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Dosage:5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Was able to reduce the tumor volume to below baseline, whereas neither Topotecan (HY-13768) (0.83 mg/kg, i.p., BIW x 3) nor Irinotecan (HY-16562) (33 mg/kg, i.v., Q1W x 3) could achieve this.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female C.B-17 SCID mice (5-6 weeks old) subcutaneously injected with SHP-77 cells[1]
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Dosage:1, 3, and 5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Exhibited no in vivo potency in SHP-77 xenografts, where c-Kit expression is negligible, confirming its c-Kit driven property.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female Hsd: Athymic Nude-Foxn1nu mice subcutaneously implanted with CTG-1252 tumors[1]
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Dosage:1, 3, and 5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Dose-dependently inhibited tumor growth.
Achieved 70 days of complete regression at 5 mg/kg.
Induced no body weight loss but rather an increase as tumor size enlarges.
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Animal Model:Female Hsd: Athymic Nude-Foxn1nu mice subcutaneously implanted with CTG-2093 tumors[1]
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Dosage:1, 3, and 5 mg/kg
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Administration:i.v., Q1W x 3
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Result:Induced tumor stasis until day 27 with TGI of 84.8% at 5 mg/kg.
Induced no body weight loss but rather an increase as tumor size enlarges.
| NCT Number | Sponsor | Condition | Start Date |
Phase
|
|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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Appearance Liquid
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SMILES
[NN3201]
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Envío
Shipping with dry ice.
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Almacenamiento
-80°C, protect from light
Pureza y Documentación
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Ficha de datos (283 KB)
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SDS (251 KB)
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Instrucciones de manejo (2659 KB)
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
NN3201 Related Classifications
HY-177578 Related Classifications
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