Noraramtide

CD38; natural killer (NK) cells

这是一项正在进行的试验（NCT04634435），中位随访时间为191天。我们在此报告前5名患者的ARMored CIML NK的体内扩增和功能特征数据。CIML NK细胞以100%的成功率制造，并在200mg/m 2美法仑给药后24小时以5-10x10 6个细胞/kg体重的目标剂量输注。患者接受3.9-6.0x10 6/Kg干细胞。基于中性粒细胞计数恢复的植入发生在D+12-D+14。从D+7（从12%到42%）到D+28，外周血中的NK细胞扩增了3倍，一直持续到D+60（占总PBMC的25%，图1A）。大多数扩增的NK细胞为CD56-dim、CD16-high、KIR high和CD57-high。CD57和KIR表达从D+7到D+60随时间增加，而NKG2A表达降低，表明成熟、活化和细胞毒性NK细胞的扩增。调节性T细胞在D+7时增加（3%比总PBMC的15%），并在D+14后恢复到基线水平，这很可能反映了IL-2治疗的效果。在体外针对MOLP8 MM细胞系测试了输注产品的功能容量。与未经处理的CIML NK细胞相比，BHV-1100 ARM转染的CIML NK细胞显示出IFN（0H时53%对48%，24小时时53%对44%）和CD107a（图1B）（0H时26%对13%，24小时时34%对15%）产量的增加，并且该产品在24小时内是稳定的。 结论：自体BHV-1100 ARMored CIML NK细胞在输注后具有增强的抗MM活性，并在D+28时扩增并持续体内峰值。这代表了一种在ASCT背景下促进自体癌症免疫监测的创新方法。除了预期的输液反应外，没有发现严重/意外的不良事件；需要更长的随访时间来评估安全性和有效性[1]。

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.

[1]. Expansion, persistence, and characteristics of autologous, Bhv-1100 armored memory-like NK cells infused prior to autologous stem cell transplant in MRD+ multiple myeloma patients: a first-in-human trial[J]. Blood, 2023, 142: 2105.

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.

C210H300N48O65S3

4633.11

4632.08743

2580150-96-3

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

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

Typically exists as solid at room temperature

-1.1

1770 Ų

54

73

107

326

11200

33

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

MPUUPFIIXNZYOV-MIGWSOMKSA-N

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

(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

BHV-1100; Noraramtide; BHV1100; noraramtide [INN]; NORARAMTIDE [USAN]; BHV 1100; KP1237; 7YQ5294J86; KP-1237; 2580150-96-3

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。