The concept of drugs made with the gut microbiota and its components and the method of their administration to obtain effective therapeutic effects

Abstract

The present invention pertains to the concept of the formulation of biotherapeutic drugs (of a biotherapeutic drug comprising a plurality of microorganisms), which includes, but is not limited to live biotherapeutic products (LBPs) especially in the form of New (Next) Generation Biotherapeutics (NGBs), and to the concept of the administration regimen of such drugs, but also other-microbiota based drugs, especially other LBPs and faecal microbiota transplants (FMT).

Description

[0001] THE CONCEPT OF DRUGS MADE WITH THE GUT MICROBIOTA AND ITS COMPONENTS AND THE METHOD OF THEIR ADMINISTRATION TO OBTAIN EFFECTIVE THERAPEUTIC EFFECTS

[0002] TECHNICAL FIELD

[0003] The present invention pertains to the concept of the formulation of biotherapeutic drugs (of a biotherapeutic drug comprising a plurality of microorganisms), which includes, but is not limited to live biotherapeutic products (LBPs) especially in the form of New (Next) Generation Biotherapeutics (NGBs), and to the concept of the administration regimen of such drugs, but also other-microbiota based drugs, especially other LBPs and faecal microbiota transplants (FMT).

[0004] BACKGROUND

[0005] Given the complexity and variability of the microbiota, identifying individual microorganisms (strains, species, genera, etc.) and the role that they play in diseases (either positive or negative) is extremely challenging. However, approaches such as fecal microbiota transplants (FMT) or Live Biotherapeutic Products (LBPs) or their modalities (like presented herein New (Next) Generation Biotherapeutic [NGB] being a form of LBP with “smart drug” properties) have been successful in reducing the burden of some diseases. Despite potential benefits, introduction of largely undefined microbial consortia present certain risks and have proven to be a regulatory challenge. This has prompted a move towards live biotherapeutics, which are live microorganisms (individually or in defined consortia) that are used for the prevention, cure or treatment of disease or status.

[0006] Biotherapeutic drugs, often referred to as microbiome-based therapies, comprise a plurality of gut microorganisms. These innovative therapies aim to treat a variety of diseases and conditions by modulating the gut microbiota. Typically, these therapeutic compositions include a diverse consortium of beneficial bacteria naturally found in the human gastrointestinal tract. By restoring or enhancing the balance of these microorganisms, biotherapeutic drugs can significantly contribute to the management and potential cure of conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Clostridium difficile infections, and metabolic disorders like obesity and type 2 diabetes. Emerging research also suggests their potential in treating neurological conditions, such as autism spectrum disorders and depression, by influencing the gut-brain axis. This novel therapeutic strategy leverages the symbiotic relationship between humans and their gut microbiota, offering a promising avenue for precision medicine and personalized healthcare. Within the context of this invention, a biotherapeutic drug is a biotechnological medication composed of a plurality of strain-specific microorganisms, naturally found in the human or animal gastrointestinal tract. This biotherapeutic drug is designed to restore or enhance the balance of microorganisms in the gastrointestinal tract and may be beneficial in treating different gut-related and unrelated conditions.

[0007] The experience of the inventor of this patent application shows that not only the composition of a specific drug is important - whether it is a biotherapeutic in the broad sense (LBP - e.g. New Generation Biotherapeutic which cures the disease and rebuilds full microbiota ecosystem) or FMT or their various forms - but also the formula and methodology of administration of a given drug. Treatment with microbiome-based therapies has its own characteristics, which often differ from other forms of therapy known to us. The sequentiality of therapy, the order of administration of individual forms of therapy, inducing appropriate biological and clinical effects at a given moment of therapy are important.

[0008] SUMMARY OF THE INVENTION

[0009] The invention is specified by the appended patent claims.

[0010] BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 shows a conceptual scheme of biotherapeutic, LBP in a special form of NGB in version having living microorganisms and non-living microbiota components.

[0012] Figure 2 shows a conceptual scheme of biotherapeutic, LBP in a special form of NGB in version having living microorganisms only encoding in their genomes non-living microbiota elements.

[0013] DETAILED DESCRIPTION OF THE INVENTION

[0014] A New-Generation Biotherapeutic or Next-Generation Biotherapeutic (NGB) is a first- in-class drug composed of living, metabolically active artificial / synthetic gut microbiota (Synthetic Intestinal Microbiota - SIM) isolated from gut microbiota donor / s and manufactured with donor-independent manner and / or other microbiota components (phages, metabolites and peptides / proteins) or containing a genetic cargo (functional potential what is most important, definitely more than taxonomic potential / composition) producing the desired metabolites, peptides / proteins and / or phage sequences for comprehensive treatment that could be a treatment of infectious diseases (like C. difficile infections), non-communicable diseases, antibiotic resistant bacteria decolonization, immunomodulation and repopulation the patient's microbiome with desired functional potential carried within bacteria, archeons, viruses and / or microbiota components.

[0015] The drug (NGB) described herein is precisely designed and comprises (or alternatively consists of) components that give the highest probability of exerting the desired clinical effect, enhancing the effect of the drug's composition itself. However, the treatment modality, as a sequence of events, may apply not only to NGB (LBP form) presented here, but also to other microbiome therapies, particularly FMT.

[0016] NGB as a drug concept presented herein is an original, precisely designed therapy formula composed of elements described below.

[0017] The treatment modality, treatment regimen is an original, sequential, two-phase treatment protocol.

[0018] NGB as a drug concept, comprises (or alternatively consists of), as shown in Figure 2:

[0019] - biosynthetic intestinal microbiota (bSIM), comprising (or alternatively consisting of) at least two, preferably 10, 50, 100, 200 or 300 or any number within those numbers or more than 300 strains of bacteria carrying particular functional potential, selected to compose the drug (Inventor is predicting aforementioned bSIM composition on its own Drug Discovery platform called "MicroDrug" but it could be its equivalent (having the computational part, based on high- throughput computations and bioinformatics prediction of the composition of bSIM or could also be done manually, empirically)) originating entirely or mostly from donors whose complete fecal microbiota (as fecal microbiota transplantation) had a positive effect in a given clinical indication (selected mostly, but not exclusively, in proof-of-concept studies),

[0020] - quantitatively enriched selected taxa (EnTx) carrying selected functions which, according to machine learning models, artificial intelligence, and bioinformatic predictions or in vitro or in vivo observations, have a particularly strong impact on changing a given phenotype (disease, condition) in a patient. Selected taxa may vary depending on the treatment phase (depletion of residual microbiota or repopulation and rejuvenation of intestinal microbiota):

[0021] + “enriched taxa” in the 1stphase of treatment with NGB (or other microbiota-based drugs) called herein as depletion phase include taxa that have an inhibitory effect on the patient's residual microbiota, e.g. by producing antibacterial peptides, metabolites, toxins directed against the patient's residual microbiota, especially "gatekeepers" defined as taxa of the patient's residual microbiota that hinder the engraftment of healthy, newly ingested intestinal microbiota or + “enriched taxa” in the 2ndphase of treatment with NGB (or other microbiota-based drugs) called herein as repopulation and rejuvenation phase, include taxa that have a positive effect on the nutrition of the intestinal wall, especially colonocytes, on tight-junction-reducing intestinal permeability, on reproducing colonization resistance to pathobionts and / or pathogens, on reproducing proper interactions with the patient's immune system, especially when it comes to tonic stimulation, and others, in general meaning repopulation of the microbiota with the NGB or other microbiota based product taxons carrying particular functions and / or particular components.

[0022] NGB may additionally comprise (or alternatively, consist of) (version 1 of NGB, as shown in Figure 1):

[0023] - bacteriophages, antibacterial proteins / peptides, antibiotics / lantibiotics - for administration in the depletion phase for the destruction of the patient's residual microbiota and / or

[0024] - metabolites - serving, among others, for nourishing the intestinal wall (e.g. short-chain fatty acids), restoring the proper acid-base balance and intestinal pH, inhibiting pathogens / pathobionts (e.g. bile salts and others), and other purposes.

[0025] To maximize the effectiveness of NGB, but it is important to claim that it is also applicable to other microbiota-based medications, especially FMT (in such cases NGB should be replaced by FMT or other microbiota-based therapy) its administration scheme was developed based on knowledge of mechanics, network ecology, colonization resistance, dynamics and mathematical models describing the probability of engrafting a healthy microbiota in place of the injured one.

[0026] The NGB but also other microbiota-based medications, especially FMT (in such cases NGB should be replaced by FMT or other microbiota-based therapy), administration regimen is two-phase treatment (Figures 1 and 2, bottom part).

[0027] The first phase, called the depletion phase, aims to decolonize the patient's residual microbiota, in particular the so-called “gatekeeper” strains, i.e. bacteria that inhibit the possibility of bSIM engraftment. Gatekeepers include E. coli, P. aeruginosa, K. pneumoniae, Enterococci, i.e. bacteria from the ESKAPE group, but also others. In the depletion phase, the goal is to maximally deplete the digestive tract and / or remove the gatekeepers. In this phase, an antibiotic is administered (e g. vancomycin, fidaxomicin or other antibiotics from the group of glycopeptides, macrocyclic antibacterial drugs or beta-lactams with metronidazole, or antibiotics containing antibiotic-resistant bacteria in their spectrum, such as colistin, gentamicin, or completely newly synthesized antibiotics with activity primarily against “gatekeeper” strains, especially those non-absorbable from the gastrointestinal tract) and additionally (if applicable, especially in NGB) components of the intestinal microbiota with antibacterial activity, inhibiting the patient's residual microbiota, in particular “gatekeepers”. These components may be a bSIM with enriched taxa having an inhibitory effect on the patient's residual microbiota, in particular those taxa containing genes that determine the production of lantibiotics or other antibacterial substances. The components may also be a cocktail of bacteriophages that act on “gatekeepers” or individual groups of bacteria that are wanted to be removed, e.g. toxin-producing strains of C. difficile, C. perfringens and others, as well as antibacterial proteins, lantibiotics, phage proteins with antibacterial activity and other components of the microbiota that may lead to the depletion of the patient's residual microbiota, in particular, lead to the removal of “gatekeepers” and reduce the overall titer of the bacterial load in the patient's intestine.

[0028] Additionally, in the depletion phase a laxatives or other microbiota / bowel cleansing preparations or methods are used to deplete the microbiota titers, especially those living within the gut mucosa area.

[0029] The depletion phase lasts 5-6 days, but may last more or less days.

[0030] Additionally, in the depletion phase and in the next, second phase, metabolites and organic compounds may be administered, which are an energy source for colonocytes (e.g. short chain fatty acids) and rebuild proper tight-junctions to minimize intestinal permeability and prevent possible translocation of toxins or live bacteria into the bloodstream or surrounding tissues.

[0031] The second phase, called the phase of repopulation and rejuvenation / nourishment of the intestine, aims to restore the proper ecology of the intestinal microbiota with selected bacteria and\or other live microbiota carrying particular functions in their genomes, and aims to rebuild the correct tight junctions of colonocytes and the intestinal wall, ensure proper nutrition of the intestinal wall and restore normal microbiota-host interactions, in particular in terms of interactions with immune system, nervous system and hormonal and paracrine effects. In this phase, the NGB part (or other microbiota-based drug, especially herein NGB could be replaced by FMT), consisting of bSIM and enriched taxa having particularly important functionalities in a given clinical or medical indication is administered - e g., to decolonize antibiotic-resistant bacteria, C. difficile, which have a particular impact on the interaction with the immune and nervous systems, or for different purposes to generally engraft desired functions and / or taxons being a drug / microbiota-based medicines components, and in particular to rebuild the healthy microbiome and desired ecologic phenomena, e.d. “colonization resistance” or others. Additionally, as described above, metabolites, especially energy sources for colonocytes, may be administered. The main goal of this phase is to rebuild or build the correct network ecology within the intestinal microbiota, microbiota-host interactions, restoring a colonization resistance mechanism, and others. This phase lasts 8-9 days (but may last for a smaller or larger number of days), up to a total of 14 days of NGB (or other microbiotabased treatments, especially other LBPs and FMT) treatment, but may last for a smaller or larger number of days.

Claims

CLAIMS1. A biotherapeutic drug formulation comprising a plurality of microorganisms, in a form of live biotherapeutic products (LBPs) such as New (Next) Generation Biotherapeutics (NGBs), wherein the formulation is designed to restore or enhance the balance of microorganisms in the gastrointestinal tract and includes:- biosynthetic intestinal microbiota (bSIM) comprising at least two strains of bacteria or other microorganisms carrying particular functional potential, selected to compose the drug, and- quantitatively enriched selected taxa (EnTx) within bSIM, carrying selected functions that impact a given phenotype in a patient, with variations depending on the treatment phase.

2. The formulation of claim 1, comprising a plurality of microorganisms isolated from the donor and manufactured in donor-independent manner, which includes, but is not limited to live biotherapeutic products (LBPs) especially in the form of New (Next) Generation Biotherapeutics (NGBs) being a specific, most advanced form of LBP in the form of a "smart drug", which means that the drug has general properties - e g. restoring the entire functional and / or taxonomic spectrum of the microbiota or at least most of it, and simultaneously has properties targeted at a specific disease or condition, restoring ecological, network, evolutionary or other mechanisms that are responsible for maintaining health and homeostasis in a healthy microbiota -composed of these microorganisms grouped (physically or purely ideologically) into the following compartments: biosynthetic intestinal microbiota (bSIM), comprising at least two, preferably 10, 50, 100, 200 or 300 or any number within those numbers or more than 300 strains of bacteria (or other microorganisms) carrying particular functional potential, selected to compose the drug originating entirely or mostly from donors, quantitatively enriched selected taxa (EnTx) within bSIM, carrying selected functions which have a particularly strong impact on changing a given phenotype (disease, condition) in a patient. Selected taxa carrying particular functional potential may vary depending on the treatment phase (depletion of residual microbiota or repopulation and rejuvenation of intestinal microbiota) and could be grouped as: o “enriched taxa” in the 1stphase of treatment called herein as depletion phase include taxa that have an inhibitory effect on the patient's residual microbiota, e g. by producing antibacterial peptides, metabolites, toxins directed against the patient's residual microbiota, especially "gatekeepers" defined as taxa of the patient's residualmicrobiota that hinder the engraftment of healthy, newly ingested intestinal microbiota or o “enriched taxa” in the 2ndphase of treatment called herein as repopulation and rejuvenation phase, include taxa that have a positive effect on the nutrition of the intestinal wall, especially colonocytes, on tight-junction-reducing intestinal permeability, on reproducing colonization resistance to pathobionts and / or pathogens, on reproducing proper interactions with the patient's immune system, especially when it comes to tonic stimulation, and others, in general meaning repopulation of the microbiota with the NGB or other microbiota based product taxons carrying particular functions and / or particular components.

3. The formulation of biotherapeutic drugs comprising a plurality of microorganisms isolated from the donor and manufactured in donor-independent manner as presented in claim 1 or 2, additionally comprising bacteriophages, antibacterial proteins / peptides, antibiotics / lantibiotics for administration in the depletion phase for the destruction of the patient's residual microbiota.

4. The formulation of biotherapeutic drugs comprising a plurality of microorganisms isolated from the donor and manufactured in donor-independent manner as presented in claim 1 or 2, additionally comprising metabolites serving, among others, for nourishing the intestinal wall (e g. short-chain fatty acids), restoring the proper acid-base balance and intestinal pH, inhibiting pathogens / pathobionts (e.g. bile salts and others), and other purposes.

5. An administration regimen for a microbiota-based drug, including LBPs, NGBs, probiotics, synthetic microorganisms, engineered microorganisms or substances derived from the intestines, comprising: a depletion phase lasting 5-6 days, aimed at decolonizing the patient's residual microbiota, particularly "gatekeepers," using antibiotics, microbiota components with antibacterial activity, bacteriophages, and / or bowel cleansing methods, and a repopulation and rejuvenation phase lasting 8-9 days, aimed at restoring the intestinal microbiota's ecology, rebuilding tight junctions, and ensuring proper microbiota-host interactions using NGBs, other microbiota-based drugs, FMT, probiotics, and / or metabolites.

6. The administration regimen of claim 5, wherein the depletion phase includes the use of antibiotics administered orally or via other routes, targeting specific bacterial strains or more broadly, and may involve the use of laxatives or other bowel cleansing preparations.

7. The administration regimen of claim 5 or 6, wherein the repopulation and rejuvenation phase involves the administration of NGBs consisting of bSIM and enriched taxa with functionalities tailored to the clinical indication, as well as other microbiota-based drugs, FMT or non-living microbiota components.

8. An administration regimen of claim 5, 6 or 7, for a drug, such as microbiota-based, as LBP, NGB claimed herein, probiotics, “new generation” probiotics, synthetic microorganisms, bioengineered microorganisms, and / or a substance of human origin derived from the intestines not classified as LBP, especially FMT, the administration regiment composed of two or more phases of treatment:- the first phase, called the depletion phase, lasting 5-6 days (but may last more or less days), aimed to decolonize the patient's residual microbiota, particularly pathogens, pathobionts, disease-specific microorganisms, and the so-called “gatekeepers”, i.e. bacteria that inhibit the possibility of microbiota / drug engraftment (which may include E. coli, P. aeruginosa, K. pneumoniae, Enterococci, i.e. bacteria from the ESKAPE group, but also others). The depletion may occur using:- an antibiotic administered orally (but in specific cases via other routes, intrarectally, intra-GI tract, intravenously when drug is released in the intestines) e g. vancomycin, fidaxomicin or other antibiotics from the group of glycopeptides, macrocyclic antibacterial drugs or beta-lactams with metronidazole, or antibiotics containing antibiotic-resistant bacteria in their spectrum, such as colistin, gentamicin, or completely newly synthesized antibiotics with activity primarily against “gatekeeper” strains (especially those non-absorbable from the gastrointestinal tract) and / or additionally (if applicable, especially in NGB)- components of the intestinal microbiota with antibacterial activity, inhibiting the patient's residual microbiota, in particular “gatekeepers”. These components may be a bSIM with enriched taxa having an inhibitory effect on the patient's residual microbiota, in particular those taxa containing genes that determine the production of lantibiotics or other antibacterial substances, and / or- microbiota components as a cocktail of bacteriophages that act on “gatekeepers” or individual groups of bacteria or other microorganisms that are wanted to be removed, e.g. toxin-producing strains of C. difficile, C. perfringens and others, as well as antibacterial proteins, lantibiotics, phage proteins with antibacterial activity and- other components of the microbiota that may lead to the depletion of the patient's residual microbiota, in particular, lead to the removal of “gatekeepers” and reduce the overall titer of the bacterial / microorganisms load in the patient's intestine and, especially after abovementioned- laxatives or other microbiota / bowel cleansing preparations or methods used to deplete the microbiota titers, especially those living within the gut mucosa area.- the second phase, called the phase of repopulation and rejuvenation / nourishment of the intestine, lasting 8-9 days (but may last for a smaller or larger number of days) - and in total up to 14 days (but may last for a smaller or larger number of days) of treatment, aimed to restore the proper ecology of the intestinal microbiota with selected bacteria and / or other live microbiota components carrying particular functions in their genomes, and / or not-living microbiome components, and aimed to rebuild the correct tight junctions of colonocytes and the intestinal wall, ensure proper nutrition of the intestinal wall and restore normal microbiotahost interactions, in particular in terms of interactions with immune system, nervous system and hormonal and paracrine effects, and in general gut and organism homeostasis. The repopulation and / or rejuvenation phase may occur via:- the NGB part consisting of bSIM and enriched taxa having particularly important functionalities in a given clinical or medical indication to generally engraft desired functions and / or taxons being a drug / microbiota-based medicines components, and in particular to rebuild the healthy microbiome and desired ecologic phenomena, e.d. “colonization resistance” or others and / or- other microbiota-based drugs, LBPs other than claimed herein NGB, or probiotics, “new generation” probiotics, synthetic microorganisms, bioengineered microorganisms, and / or a substance of human origin derived from the intestines not classified as LBP, especially FMT and. or- metabolites and non-living microbiota components, especially energy sources for colonocytes (e.g. short chain fatty acids) and rebuilding proper tight-junctions to minimize intestinal permeability and prevent possible translocation of toxins or live bacteria into the bloodstream or surrounding tissues.

Images