| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
CD38; natural killer (NK) cells
|
|---|---|
| ln Vivo |
This is an ongoing trial (NCT04634435) with a median follow-up of 191 days. We are herein reporting data on the in vivo expansion and functional characterization of ARMored CIML NK for the first 5 patients. CIML NK cells were manufactured with a 100% success rate and infused at a target dose of 5-10x10 6 cells/kg-body weight, 24 hours after 200 mg/m 2 melphalan administration. Patients received between 3.9-6.0x10 6/Kg stem cells. Engraftment based on recovery of neutrophil count occurred on D+12-D+14. There was a 3-fold expansion of NK cells in the peripheral blood from D+7 (from 12% to 42%) to D+28 that persisted until D+60 (25% total PBMC, Fig. 1A). Most expanded NK cells were CD56 dim, CD16 high, KIR high and CD57 high. CD57 and KIR expression increased over time from D+7 to D+60, whereas NKG2A expression decreased, indicating the expansion of mature, activated, and cytotoxic NK cells. Regulatory T cells increased by D+7 (3% vs 15% total PBMC) and returned to baseline after D+14 most likely reflecting the effect of IL-2 treatment. The functional capacity of the infused product was tested in vitro against MOLP8 MM cell line. The BHV-1100 ARMored CIML NK cells showed increased IFN (53% vs 48% at 0H and 53% vs 44% at 24H) and CD107a (Fig.1B) (26% vs 13% at 0H and 34% vs 15% at 24H) production compared to untreated CIML NK cells and the product was stable for 24 hours.
Conclusion: Autologous, BHV-1100 ARMored CIML NK cells have enhanced anti-MM activity as well as expand and persist in vivo peaking at D+28 after infusion. This represents an innovative approach to boost autologous cancer immunosurveillance in the context of ASCT. Aside from anticipated infusion reactions, no severe/unexpected adverse events were noted; longer follow-up is required to assess safety and efficacy [1].
|
| Animal Protocol |
Researchers designed a first-in-human study of autologous CIML NK cells coated ex-vivo with BHV-1100 for MRD+, MM patients undergoing ASCT following first or second remission. NK cells were isolated from non-mobilized leukapheresis on day -1 (prior to melphalan for HCT) using CD3 depletion followed by CD56 positive selection with Miltenyi's CliniMACS. The NK cells were incubated overnight (12-16 hours) with IL-12 (10ng/ml), IL-15 (100ng/ml), and IL-18 (50ng/ml) to induce CIML differentiation, washed and subsequently coated with BHV-1100 for one hour prior to infusion. The product was infused fresh on D0 after standard melphalan 200 mg/m2 myeloablative conditioning and followed by stem cell infusion. Low dose IL2 (1 mIU/m 2) was administered SQ starting on D+1, QOD for a total of 7 doses.
|
| References | |
| Additional Infomation |
KP1237 is a antibody-redirecting molecule composed of two binding sites (a CD38 binder and a universal antibody binding terminus binder) connected by a linker chain.
Noraramtide is a synthetic, small, bispecific antibody-redirecting/recruiting molecule (ARM) that recognizes the tumor-associated antigen (TAA) and cell surface glycoprotein CD38 on tumor cells with its target binding terminus (TBT) and, through connection by a tunable linker domain, recognizes endogenous antibodies already present in the patient's blood with its universal antibody binding terminus (uABT), with potential immunomodulating and antineoplastic activities. Upon administration, noraramtide simultaneously targets and binds to CD38 expressed on tumor cells with its TBT and to endogenous antibodies with its uABT. This recruits immune effector cells, such as the patient's activated natural killer (NK) cells, to eliminate the CD38-expressing tumor cells through antitumoral antibody-dependent cellular cytotoxicity (ADCC). CD38, a type II transmembrane glycoprotein, is present on various immune cells and hematologic malignancies. Its expression has been correlated with poor prognosis. |
| Molecular Formula |
C210H300N48O65S3
|
|---|---|
| Molecular Weight |
4633.11
|
| Exact Mass |
4632.08743
|
| CAS # |
2580150-96-3
|
| Sequence |
Ala-Arg-{2-aminoheptanoicacid}-Tyr-His-Asp-Gly-Val-Leu-{Phe(4-phenyl)}-{2-aminoheptanoicacid}-{d-Cys(s-carboxymethyl)}-{XGly}-{γGlu}-{γGlu}-{d-γGlu}-{γGlu}-{γGlu}-Gly-Gly-Asp-Cys-Ala-Trp-His-Leu-Gly-Glu-Leu-Val-Trp-Cys-Thr (Sulfidebridge:Ala1-Cys13,Disulfidebridge:Cys24-Cys34) X= NH2-PEG6-((6S)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6-yl)methyl hydrogen carbonate-piperidine-4-carboxylic acid
|
| SequenceShortening |
AR-{2-aminoheptanoicacid}-YHDGVL-{Phe(4-phenyl)}-{2-aminoheptanoicacid}-{d-Cys(s-carboxymethyl)}-{XGly}-{γGlu}-{γGlu}-{d-γGlu}-{γGlu}-{γGlu}-GGDCAWHLGELVWCT (Sulfidebridge: Ala1-Cys13,Disulfidebridge:Cys24-Cys34) X= NH2-PEG6-((6S)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6-yl)methyl hydrogen carbonate-piperidine-4-carboxylic acid
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
-1.1
|
| Hydrogen Bond Donor Count |
54
|
| Hydrogen Bond Acceptor Count |
73
|
| Rotatable Bond Count |
107
|
| Heavy Atom Count |
326
|
| Complexity |
11200
|
| Defined Atom Stereocenter Count |
33
|
| SMILES |
CCCCC[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSCC(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCCNC(=N)N)C)C(=O)NCCOCCOCCOCCOCCOCCOCCN2C3=C(CC[C@H]4[C@H]([C@H]4COC(=O)N5CCC(CC5)C(=O)NCC(=O)N[C@@H](CCC(=O)N[C@H](CCC(=O)N[C@H](CCC(=O)O)C(=O)N[C@H](CCC(=O)N[C@H](CCC(=O)NCC(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H]6CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC6=O)C)CC7=CNC8=CC=CC=C87)CC9=CNC=N9)CC(C)C)CCC(=O)O)CC(C)C)C(C)C)CC1=CNC4=CC=CC=C41)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)C(=O)O)C(=O)O)C(=O)O)C(=O)O)CC3)N=N2)CC(=O)O)CCCCC)CC1=CC=C(C=C1)C1=CC=CC=C1)CC(C)C)C(C)C)CC(=O)O)CC1=CN=CN1)CC1=CC=C(C=C1)O
|
| InChi Key |
MPUUPFIIXNZYOV-MIGWSOMKSA-N
|
| InChi Code |
InChI=1S/C210H300N48O65S3/c1-16-18-21-36-136-186(288)241-149(86-119-41-45-127(260)46-42-119)192(294)243-153(90-126-97-214-109-225-126)196(298)245-154(91-173(275)276)183(285)223-102-169(269)252-176(113(9)10)202(304)247-146(83-111(5)6)190(292)242-148(85-118-39-43-121(44-40-118)120-30-23-20-24-31-120)191(293)236-137(37-22-19-17-2)187(289)246-156(93-175(279)280)198(300)249-157(104-324-107-170(270)226-115(13)179(281)234-138(185(287)235-136)38-29-65-216-209(211)212)184(286)215-66-70-317-72-74-319-76-78-321-80-81-322-79-77-320-75-73-318-71-69-258-160-56-48-131-130(47-49-135(160)255-256-258)132(131)103-323-210(316)257-67-63-122(64-68-257)181(283)221-100-168(268)232-143(206(310)311)52-59-163(263)231-142(205(308)309)51-58-162(262)228-139(54-61-171(271)272)188(290)237-144(207(312)313)53-60-164(264)230-141(204(306)307)50-57-161(261)219-98-165(265)220-99-166(266)233-155(92-174(277)278)197(299)250-158-105-325-326-106-159(201(303)254-178(117(15)259)208(314)315)251-194(296)151(88-124-95-218-134-35-28-26-33-129(124)134)248-203(305)177(114(11)12)253-199(301)147(84-112(7)8)240-189(291)140(55-62-172(273)274)229-167(267)101-222-182(284)145(82-110(3)4)239-195(297)152(89-125-96-213-108-224-125)244-193(295)150(238-180(282)116(14)227-200(158)302)87-123-94-217-133-34-27-25-32-128(123)133/h20,23-28,30-35,39-46,94-97,108-117,122,130-132,136-159,176-178,217-218,259-260H,16-19,21-22,29,36-38,47-93,98-107H2,1-15H3,(H,213,224)(H,214,225)(H,215,286)(H,219,261)(H,220,265)(H,221,283)(H,222,284)(H,223,285)(H,226,270)(H,227,302)(H,228,262)(H,229,267)(H,230,264)(H,231,263)(H,232,268)(H,233,266)(H,234,281)(H,235,287)(H,236,293)(H,237,290)(H,238,282)(H,239,297)(H,240,291)(H,241,288)(H,242,292)(H,243,294)(H,244,295)(H,245,298)(H,246,289)(H,247,304)(H,248,305)(H,249,300)(H,250,299)(H,251,296)(H,252,269)(H,253,301)(H,254,303)(H,271,272)(H,273,274)(H,275,276)(H,277,278)(H,279,280)(H,306,307)(H,308,309)(H,310,311)(H,312,313)(H,314,315)(H4,211,212,216)/t115-,116-,117+,130-,131+,132-,136-,137-,138-,139+,140-,141+,142+,143-,144+,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,176-,177-,178-/m0/s1
|
| Chemical Name |
(2R)-2-[[(4R)-4-[[(2R)-2-[[(4R)-4-[[(4S)-4-[[2-[[1-[[(4R,5R,6S)-12-[2-[2-[2-[2-[2-[2-[2-[[(3R,6S,9S,12S,15S,18S,24S,27S,30S,33S,36S,39S)-36-(3-carbamimidamidopropyl)-6,24-bis(carboxymethyl)-30-[(4-hydroxyphenyl)methyl]-27-(1H-imidazol-5-ylmethyl)-39-methyl-15-(2-methylpropyl)-5,8,11,14,17,20,23,26,29,32,35,38,41-tridecaoxo-9,33-dipentyl-12-[(4-phenylphenyl)methyl]-18-propan-2-yl-1-thia-4,7,10,13,16,19,22,25,28,31,34,37,40-tridecazacyclodotetracontane-3-carbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-10,11,12-triazatricyclo[7.3.0.04,6]dodeca-1(9),10-dien-5-yl]methoxycarbonyl]piperidine-4-carbonyl]amino]acetyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-5-[[2-[[2-[[(2S)-3-carboxy-1-[[(4R,7S,10S,13S,16S,22S,25S,28S,31S,34R)-16-(2-carboxyethyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-25-(1H-imidazol-4-ylmethyl)-7,28-bis(1H-indol-3-ylmethyl)-31-methyl-13,22-bis(2-methylpropyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-34-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-5-oxopentanoic acid
|
| Synonyms |
BHV-1100; Noraramtide; BHV1100; noraramtide [INN]; NORARAMTIDE [USAN]; BHV 1100; KP1237; 7YQ5294J86; KP-1237; 2580150-96-3
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| 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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2158 mL | 1.0792 mL | 2.1584 mL | |
| 5 mM | 0.0432 mL | 0.2158 mL | 0.4317 mL | |
| 10 mM | 0.0216 mL | 0.1079 mL | 0.2158 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
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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