Nangibotide

Nangibotide

LQEEDAGEYGCM-amide

CAS 2014384-91-7

• Molecular FormulaC₅₄H₈₂N₁₄O₂₂S₂
• Average mass1343.439 Da
• 2014384‐91‐7

• L-Leucyl-L-glutaminyl-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methioninamide
• LR 12 peptide
• LQEEDAGEYG CM

L-Leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methionine
L-Methionine, L-leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-нангиботидمانغيبوتيد南吉博肽

• OriginatorInotrem
• ClassAnti-infectives; Anti-inflammatories; Anti-ischaemics; Antivirals; Peptides
• Mechanism of ActionTREML1 protein inhibitors

• Phase II/IIICOVID 2019 infections
• Phase IISeptic shock
• Phase IMyocardial infarction

• 12 Jul 2021Inotrem has patents pending for nangibotide use in severe forms of COVID-19
• 12 Jul 2021Inotrem receives funding from French government by Bpifrance for nangibotide development in COVID-2019 infections
• 12 Jul 2021Inotrem receives authorization from both the French and Belgian authorities to proceed with clinical development of nangibotide up to registration in COVID-2019 infections

Nangibotide, also referred as LR12, is an antagonist of triggering receptor expressed on myeloid cells (TREM)-1, and was derived from residues 94 to 105 of TREM-like transcript-1 (TLT-1).

TREM-1 plays a crucial role in the onset of sepsis by amplifying the host immune response. TLT-1– and TLT-1–derived peptides therefore exhibit anti-inflammatory properties by dampening TREM-1 signalling.  LR12 blocks TREM-1 by binding to the TREM-1 ligand and provides protective effects during sepsis such as inhibiting hyper-responsiveness, organ damage, and death, without causing deleterious effects. The protective effects of modulating TREM-1 signalling are also evident in other models of inflammation such as: pancreatitis; haemorrhagic shock; inflammatory bowel diseases and inflammatory arthritis

Inotrem is developing the peptide nangibotide, a triggering receptor expressed on myeloid cells 1 inhibitor, for treating sepsis and septic shock. In July 2021, this drug was reported to be in phase 3 clinical development.

Nangibotide is an inhibitor of TREM-1, a receptor found on certain white blood cells. Activation of TREM-1 stimulates inflammation. Nangibotide is therefore being investigated as a treatment for the overwhelming inflammation typically seen in severe sepsis.

Mode of action

TREM-1 is a receptor found on neutrophils, macrophages and monocytes, key elements of the immune system. Activation of TREM-1 results in expression of NF-κB, which promotes systemic inflammation. Nangibotide inhibits TREM-1, thereby preventing the inflammatory activation. Absence of TREM-1 results in vastly reduced inflammation without impairing the ability to fight infection.^[2]

Animal models

LR17, a mouse equivalent of nangibotide, improves survival in mouse models of severe sepsis.^[3] In a pig model of sepsis, LR12 – another animal equivalent of nangibotide – resulted in significantly improved haemodynamics and less organ failure.^[4] In monkeys, LR12 also reduced the inflammatory and hypotensive effects of sepsis.^[5]

Human studies

Nangibotide has demonstrated safety in Phase 1 (healthy volunteers)^[6] and Phase 2 (sick patients with septic shock)^[7] studies. The ASTONISH trial will examine clinical efficacy in 450 patients with septic shock.^[8]

Inotrem Receives Approval to Expand Nangibotide Clinical Trial in Critically Ill COVID-19 Patients and Receives Additional Public Funding of €45 Million

• Inotrem’s phase 2/3 clinical trial “ESSENTIAL” will enroll up to 730 patients in Europe to demonstrate the safety and efficacy of nangibotide to treat critically ill COVID-19 patients with respiratory failure.
• Recent preclinical studies have strengthened the body of evidence for targeting the TREM-1 pathway which is activated in a subset of patients suffering from severe COVID-19.

July 12, 2021 03:00 AM Eastern Daylight Time

PARIS–(BUSINESS WIRE)–Inotrem S.A., a biotechnology company specializing in the development of immunotherapies targeting the TREM-1 pathway, announces that it has obtained authorization to pursue the clinical development of nangibotide up to registration in COVID-19 patients from both the French and Belgian competent authorities.

As part of this program, Inotrem receives additional 45 million euros in public funding under the “Capacity Building” Call for Expression of Interest, operated on behalf of the French government by Bpifrance, the French national investment bank, as part of the Programme d’investissements d’avenir (PIA) and the France Recovery Plan, bringing French state support for the project to a total of 52,5 million euros. This public funding will support Inotrem’s clinical program including the phase 2/3 study “ESSENTIAL” which aims to demonstrate the efficacy and safety of nangibotide in treating patients in respiratory distress with severe forms of COVID-19.

The primary endpoint is evaluation of the impact of nangibotide on the progression of disease in patients receiving ventilatory support due to COVID-19 as well as on the severity of the respiratory failure, duration of mechanical ventilation, length of stay in intensive care and mortality. In “ESSENTIAL”, a Phase 2/3 clinical program, up to 730 patients will be enrolled initially in France and Belgium and, possibly in other European countries. Pre-defined interim analyses will be conducted by an independent Data Monitoring Board to test futility and to allow for the study design to be adapted as necessary. “ESSNTIAL” is the continuation of a 60 patients phase 2a evaluating the safety and efficacy of nangibotide in patients suffering from severe COVID-19. In July 2020, the CoviTREM-1 consortium, which includes the Nancy and Limoges university hospitals and Inotrem, obtained public funding of 7,5 million euros under the “PSPC-COVID” call for projects, operated on behalf of the French government by Bpifrance

New pre-clinical studies with nangibotide have demonstrated that the administration of nangibotide in murine models infected with SARS-CoV-2 was associated with a decrease in inflammatory mediators and an improvement of clinical signs, in particular respiratory function, and survival. Inotrem also confirmed in 3 different and independent cohorts that sTREM-1, a marker of the activation of the TREM-1 biological pathway, is associated with both severity and mortality in critically ill COVID-19 patients.

Leveraging the results of these preclinical studies and the implications for the role of the TREM-1 pathway in COVID-19, Inotrem has filed additional patents to cover nangibotide use in severe forms of COVID-19 as well as the use of sTREM-1 as a biomarker and companion diagnostic. This significantly strengthens Inotrem’s already broad patent estate.

Jean-Jacques Garaud, Executive Vice-President, Head of Scientific and Medical Affairs and Inotrem’s co-founder said :“We are eager to pursue the development of nangibotide in these severe forms of COVID-19. Nangibotide is a TREM-1 inhibitor which has already demonstrated a trend towards efficacy in septic shock patients and has the potential to modulate the dysregulated immune response in critically ill COVID-19 patients. With this large clinical study, we can demonstrate efficacy for nangibotide in a further indication with the goals of reducing the duration of hospitalization and mortality.”

Sven Zimmerman, CEO of Inotrem, also declared: “The size of the financial support awarded to us as part of the French government’s initiative against COVID-19 is a testimony to the relevance of targeting the TREM-1 pathway with nangibotide in these severely ill patients. We are delighted by the confidence placed in our technology and our team. Everyone at Inotrem is fully committed to deliver on this ambitious program alongside nangibotide’s ongoing Phase 2b trial in septic shock patients.”

About Inotrem
Inotrem S.A. is a biotechnology company specialized in immunotherapy for acute and chronic inflammatory syndromes. The company has developed a new concept of immunomodulation that targets the TREM-1 pathway to control unbalanced inflammatory responses. Through its proprietary technology platform, Inotrem has developed the first-in-class TREM-1 inhibitor, LR12 (nangibotide), with potential applications in a number of therapeutic indications such as septic shock and myocardial infarction. In parallel, Inotrem has also launched another program to develop a new therapeutic modality targeting chronic inflammatory diseases. The company was founded in 2013 by Dr. Jean-Jacques Garaud, a former head of research and early development at the Roche Group, Prof. Sébastien Gibot and Dr. Marc Derive. Inotrem is supported by leading European and North American investors.

www.inotrem.com

About TREM-1 pathway
TREM-1 pathway is an amplification loop of the immune response that triggers an exuberant and hyperactivated immune state which is known to play a crucial role in the pathophysiology of septic shock and acute myocardial infarction.

About Nangibotide
Nangibotide is the formulation of the active ingredient LR12, which is a 12 amino-acid peptide prepared by chemical synthesis. LR12 is a specific TREM-1 inhibitor, acting as a decoy receptor and interfering in the binding of TREM-1 and its ligand. In preclinical septic shock models, nangibotide was able to restore appropriate inflammatory response, vascular function, and improved animals’ survival post septic shock.

About ESSENTIAL study:
The Efficacy and Safety Study Exploring Nangibotide Treatment in COVID-19 pAtients with ventiLatory support, is a randomized, double-blind, placebo-controlled confirmatory study with adaptive features that will be performed in Europe. This is a pivotal study and it is expected that based on its results, nangibotide could be registered in this indication. The first part of the study (i.e.: 60 patients) has been already finalized and assessed by an independent data monitoring committee with excellent safety results. The study will recruit up to 730 patients in up to 40 sites. Several interim and futility analyses are foreseen as part of the adaptive design of the study.

About Bpifrance
Bpifrance is the French national investment bank: it finances businesses – at every stage of their development – through loans, guarantees, equity investments and export insurances. Bpifrance also provides extra-financial services (training, consultancy.). to help entrepreneurs meet their challenges (innovation, export…).

PATENT

WO-2021144388

Process for preparing nangibotide by solid phase synthesis, useful for treating acute inflammatory disorders such as septic shock. Also claims novel peptide fragments, useful in the synthesis of nangibotide.

Example 1

Preparation of nangibotide by full SPPS (Reference)

Step 1 : Loading of the first amino acid onto the Rink Amide Resin

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min. 2 eq Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin after 5 min. All the coupling steps were conducted in this way unless described differently. The loading step was carried out for 1.5 hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of 20% piperidine solution in DMF for two 10 min cycles. This step was performed analogously for all the amino acid residues. The loading, calculated by UV absorption for the peptidyl resin, was 0.8 mmol/g.

Step 2: peptide elongation

For the coupling of all the amino acids involved in the synthesis of nangibotide, 3 eq of each amino acid were activated by 3 eq of DIC and OxymaPure dissolved in DMF at 0.3 M cone. At the end of the peptide elongation, a final Fmoc deprotection, as already described, was performed before moving to the cleavage step.

Step 3: Cleavage and precipitation of crude nangibotide

The cleavage of nangibotide off the resin was carried out using a solution of 16 mL of TFA/DODT/TIPS/water in 90/4/3/3 ratio cooled at 0°C. The peptidyl resin was added portionwise in 30 min keeping the internal temperature under 25°C. The cleavage was run for 3.5 hours, then the resin was filtered and washed by 10 mL of TFA for 10 min.

DIPE was used for the precipitation of the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried under vacuum overnight. Molar yield 40%. Purity 61%.

Example 2

Preparation of nangibotide by three-fragment condensation

In the approach using three fragments, only the cysteine residue was coupled to the methionine on rink amide resin to prepare fragment 11-12, whereas protected peptide fragments 1-7 and 8-10 were synthesized using 2-CTC resin.

Step 1: Synthesis of fragment 11-12

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min 2 eq of Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin. The loading step was carried out for 1 and half hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by

addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH to obtain resin-attached Fmoc-deprotected fragment 11-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g.

Step 2: Synthesis of fragments 1-7 and 8-10

For the synthesis of both fragments the loading of 2-chloro trityl chloride resin was performed on 5 g (1.6 mmol/g) using 0.8 eq Fmoc-Gly-OH (6.40 mmol, 1.90 g) dissolved in 30 mL of DCM and addition of 3 eq DIPEA (24 mmol, 4.19 mL). The loading step was carried out for 1 hour, then the resin was washed by 30 mL DCM for three times and eventual Cl-groups were capped by two different capping solutions: first by 30 mL of methanol/DIPEA/DCM (1:2:7) and then by 30 mL AC2O/DIPEA/DCM in the same ratio. After the treatment with these solutions for 15 min and subsequent washing with DCM, the resin was washed three times with DMF, before deprotection of Fmoc and evaluation of the resin loading. Generally, this protocol gave a resin loaded with 1.1 mmol/g Fmoc-Gly-OH. The Fmoc deprotection and coupling step protocols were equally performed with all the amino acids in the respective sequences: Fmoc-Tyr(tBu)-OH and Fmoc-Glu(tBu)-OH for fragment 8-10, and Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OtBu)-OH twice, Fmoc-Gln(Trt)-OH and Fmoc-Leu-OH for fragment 1-7.

For each coupling, 3 eq amino acid were activated by 3 eq DIC and 3 eq OxymaPure dissolved in DMF at 0.3 M cone.

Fragment Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The final solution was concentrated to 50 mL under vacuum then washed by water and brine. The organic layer was dried by anhydrous sodium sulphate, filtered and further concentrated before crystallization of the tripeptide with 5 volumes of petroleum ether at 0°C. The peptide was filtered, washed by petroleum ether and dried overnight in a vacuum oven at 37°C. Molar yield 65%. Purity 90%.

Fragment Fmoc-Leu-Gln(Trt)-Glu(OtBu)-Glu(OtBu)-Asp(OtBu)-Ala-Gly-OH (1-7) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The DCM was evaporated and replaced by methanol, adding and evaporating 30 mL methanol a couple of times till one third of the volume. The peptide fragment was precipitated by adding 5 volumes (150 mL) water to the methanol solution at 0°C and filtered after stirring for 30 min. The full protected heptapeptide was washed by water and dried overnight in a vacuum oven at 37°C. Molar yield 85%. Purity 89%.

Step 3: Synthesis of fragment 8-12 (Fragment condensation 1)

The fragment condensation between Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) and H-Cys(Trt)-Met-MBHA resin (11-12) was carried out activating 2 eq (1.6 mmol, 1.12 g) of fragment 8-10 dissolved in 6 mL of DMF at 40°C by using 2 eq OxymaPure (1.6 mmol, 0.22 g) and 2 eq DIC (1.6 mmol, 0.25 mL) for 10 min. The activated ester of tripeptide 8-10 was added to the resin-attached fragment 11-12 and stirred for 3 hours at 40°C. After filtration, the resin was washed three times by 15 mL DMF and then capped by 12 mL of AC2O 10% in DMF for 15 min. The resin was washed three timed by 12 mL DMF before deprotection of Fmoc to finally obtain resin-attached Fmoc-protected fragment 8-12. Molar yield 91%. Purity 89%.

Step 4: Synthesis of nanaibotide (Fragment condensation 2)

The fragment condensation between fragment 1-7 and H-Glu(OtBu)-Tyr(tBu)-Gly-Cys(Trt)-Met-MBHA resin (8-12) was carried out activating 1.5 eq (2.25 mmol, 2.64 g) of fragment 1-7 dissolved in 25 mL DMF at 40°C by using 2 eq OxymaPure (2.25 mmol, 0.32 g) and 2 eq DIC (2.25 mmol, 0.35 mL) for 15 min. The activated ester of fragment 1-7 was added to the resin-attached fragment 8-12 and stirred for 3.5 hours at 40°C. After filtration, the resin was washed three times by 12 mL DMF before deprotection of Fmoc with the standard procedure described above. After Fmoc deprotection, the resin was washed again by DMF and DCM and then dried at vacuum pump.

Step 5: Cleavage and precipitation of crude nanaibotide

The cleavage of nangibotide off the resin was carried out using a solution of 16 mL of TFA/DODT/TIPS/water in 90/4/3/3 ratio cooled at 0°C. The peptidyl resin was added portionwise in 30 min keeping the internal temperature under 25°C. The cleavage was run for 3.5 hours, then the resin filtered and washed by 10 mL of TFA for 10 min.

DIPE was used to precipitate the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried at vacuum pump overnight. Molar yield 61%. Purity 73%.

Example 3

Preparation of nangibotide by two-fragment condensation

In the approach using two fragments, the SPPS elongation onto MBHA resin, as described in Example 2, step 1, was continued until Glu⁸ was attached to provide fragment 8-12, then fragment 1-7, synthesized on 2-CTC resin as described in example 2, step 2, was coupled to the resin-attached fragment 8-12 as described in example 2, step 4.

Step 1: Synthesis of fragment 8-12

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min 2 eq of Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin. The loading step was carried out for 1 and half hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH; Fmoc-Glu(OtBu)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Gly-OH to obtain fragment 8-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g. Molar yield 88%. Purity 83%.

Step 2: Synthesis of nanaibotide (Fragment condensation 2)

The final fragment condensation was performed as described in example 2, step 4.

Step 3: Cleavage and precipitation of crude nanaibotide

The cleavage of nangibotide off the resin was carried out as described in example 2, step 5. Molar yield 60%. Purity 70%.

PAPER

Methods in enzymology (2000), 312, 293-304

 Journal of the American College of Cardiology (2016), 68(25), 2776-2793

PATENT

https://patents.google.com/patent/WO2011124685A1/en

Product pat, WO2011124685 ,protection in the EU states and the US  April 2031

References

1. ^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”. Br J Clin Pharmacol. 84 (10): 2270–2279. doi:10.1111/bcp.13668. PMC 6138490. PMID 29885068.
2. ^ Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, Oxenius A, Reith W, Saurer L, Mueller C (2014). “TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance”. PLOS Pathog. 10 (1): e1003900. doi:10.1371/journal.ppat.1003900. PMC 3894224. PMID 24453980.
3. ^ Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, Massin F, Max JP, Ford J, Alauzet C, Levy B, McVicar DW, Gibot S (1 June 2012). “Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis”. Journal of Immunology. 188 (11): 5585–5592. doi:10.4049/jimmunol.1102674. PMC 6382278. PMID 22551551.
4. ^ Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, Lozniewski A, Leroy P, Tran N, Gibot S (Feb 2013). “Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs”. Shock. 39 (2): 176–182. doi:10.1097/SHK.0b013e31827bcdfb. PMID 23324887. S2CID 23583753.
5. ^ Derive M, Boufenzer A, Gibot S (April 2014). “Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate”. Anaesthesiology. 120 (4): 935–942. doi:10.1097/ALN.0000000000000078. PMID 24270127. S2CID 10347527.
6. ^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”. Br J Clin Pharmacol. 84 (10): 2270–2279. doi:10.1111/bcp.13668. PMC 6138490. PMID 29885068.
7. ^ François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF (July 2020). “Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial”. Intensive Care Medicine. 46 (7): 1425–1437. doi:10.1007/s00134-020-06109-z. PMID 32468087. S2CID 218912723.
8. ^ “Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock (ASTONISH)”. ClinicalTrials.gov. US National Library of Medicine. Retrieved 13 July 2020.

Derive et al (2013) Effects of a TREM-Like Transcript 1–Derived Peptide During Hypodynamic Septic Shock in Pigs. Shock39(2) 176 PMID: 23324887

Derive et al (2014) Attenuation of Responses to Endotoxin by the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LR12 in Nonhuman Primate. Anesthesiology120(4) 935 PMID: 24270127

Derive et al (2012) Soluble Trem-like Transcript-1 Regulates Leukocyte Activation and Controls Microbial Sepsis. J. Immunol.188(11) 5585 PMID: 22551551

//////////////Nangibotide, phase 3, нангиботид , مانغيبوتيد , 南吉博肽 , INOTREM, SEPTIC SHOCK, PEPTIDE

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