Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
  • C07K16/244—Interleukins [IL]
  • C07K16/245—IL-1
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• the invention relates generally to the fields of medicine, dermatology, and immunology. More particularly, the invention relates to the use of antibodies (Abs) which specifically bind interleukin- la (IL-la) to treat various symptoms of atopic dermatitis.
• Abs antibodies which specifically bind interleukin- la (IL-la) to treat various symptoms of atopic dermatitis.
• Atopic dermatitis also known as eczema
• AD Atopic dermatitis
• eczema is an inflammatory skin disease affecting as much as 20% of the population in western industrial societies.
• Chronic eczema in AD and particularly the associated pruritus can be a significant cause of morbidity and impact life quality.
• Disease pathogenesis is complex but ultimately converges on a pathological inflammatory process that disrupts the protective barrier function of the skin.
• methods of reducing one or more symptoms of AD in a human subject can include the step of administering to the subject a pharmaceutical composition including a pharmaceutically acceptable carrier and an amount of an agent that selectively binds IL-la effective to reduce to reduce a symptom of AD in the subject.
• the agent can be an anti-IL-la antibody such as a monoclonal antibody (e.g., of the IgGl isotype), a monoclonal antibody that includes a complementarity determining region of bermekimab (MABpl), or bermekimab (MABpl).
• the pharmaceutical composition can be administered to the subject by injection, subcutaneously, intravenously, intramuscularly, or intradermally.
• the dose can be at least 50 mg (e.g., at least 50, 75, 100, 150, 200, 300, 400, 500, 600, 700, or 800 mg).
• at least 200 mg e.g., 200, 300, 400, 500, 600, 700, or 800 mg
• bermekimab is administered at least once a week (e.g., 1, 2, 3 times a week) by subcutaneous injection for at least 2 weeks (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 50 weeks) or until a symptom of AD is reduced or cleared.
• mAh formulations that include about 180, 200, 220, 240, 260, 280, 300, or more mAh per ml of the pharmaceutical composition, and mAh formulations that have a viscosity of at least about 20 cP (centipoise) at 25°C (e.g., at least 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 cP at 25°C).
• compositions containing a mAh at a concentration of about 200 mg/ml or more are also described herein.
• pharmaceutical compositions containing a mAh at a concentration of about 200 mg/ml or more pharmaceutical compositions containing a mAh that have a viscosity of at least about 20 cP at 25°C, and pharmaceutical compositions containing a mAh at a concentration of about 200 mg/ml or more and a viscosity of at least about 20 cP at 25°C.
• a mAh by increasing the concentration of the mAh to about 180, 200, 220, 240, 260, 280, 300, or more mAh per ml of the pharmaceutical composition and/or increasing viscosity of the mAb-containing pharmaceutical composition to at least about 20 cP (centipoise) at 25°C (e.g., at least 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 cP at 25°C)
• an“antibody” or“Ab” is an immunoglobulin (Ig), a solution of identical or heterogeneous Igs, or a mixture of Igs.
• An“Ab” can also refer to fragments and engineered versions of Igs such as Fab, Fab’, and F(ab’)2 fragments; and scFv’s, heteroconjugate Abs, and similar artificial molecules that employ Ig-derived CDRs to impart antigen specificity.
• a “monoclonal antibody” or“mAh” is an Ab expressed by one clonal B cell line or a population of Ab molecules that contains only one species of an antigen binding site capable of immunoreacting with a particular epitope of a particular antigen.
• A“polyclonal Ab” is a mixture of heterogeneous Abs.
• a polyclonal Ab will include myriad different Ab molecules which bind a particular antigen with at least some of the different Abs immunoreacting with a different epitope of the antigen.
• a polyclonal Ab can be a mixture of two or more mAbs.
• An“antigen-binding portion” of an Ab is contained within the variable region of the Fab portion of an Ab and is the portion of the Ab that confers antigen specificity to the Ab (i.e., typically the three-dimensional pocket formed by the CDRs of the heavy and light chains of the Ab).
• a “Fab portion” or “Fab region” is the proteolytic fragment of a papain-digested Ig that contains the antigen-binding portion of that Ig.
• a "non-Fab portion” is that portion of an Ab not within the Fab portion, e.g., an“Fc portion” or“Fc region.”
• A“constant region” of an Ab is that portion of the Ab outside of the variable region.
• the“effector portion" of an Ab is the portion of an Ab that is responsible for binding other immune system components that facilitate the immune response.
• the site on an Ab that binds complement components or Fc receptors is an effector portion of that Ab.
• an Ab or protein is purified when it is at least about 10% (e.g, 9%, 10%, 20%, 30% 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.9%, and 100%), by weight, free from the non-Ab proteins or other naturally-occurring organic molecules with which it is naturally associated. Purity can be measured by any appropriate method, e.g, column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. A chemically-synthesized protein or other recombinant protein produced in a cell type other than the cell type in which it naturally occurs is“purified.”
• bind By“bind”,“binds”, or“reacts with” is meant that one molecule recognizes and adheres to a particular second molecule in a sample, but does not substantially recognize or adhere to other molecules in the sample.
• an Ab that "specifically binds" another molecule has a Kd greater than about 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 liters/mole for that other molecule.
• An Ab that "selectively binds" a first molecule specifically binds the first molecule at a first epitope but does not specifically bind other molecules that do not have the first epitope.
• an Ab which selectively binds IL-1 alpha specifically binds an epitope on IL-1 alpha but does not specifically bind IL-lbeta (which does not have the epitope).
• a "therapeutically effective amount” is an amount which is capable of producing a medically desirable effect in a treated animal or human (e.g, amelioration or prevention of a disease or symptom of a disease).
• “about” means +/- 20 percent.
• Fig. 1 is a flow chart showing an overview of the treatment protocol of the clinical study described in the Examples section below.
• Fig. 2 is a chart showing the baseline characteristics of the study populations which participated in the clinical study described in the Examples section below.
• Fig. 3 is a chart listing the adverse events observed in the clinical study described in the Examples section below.
• Fig 4 is a study calendar of the clinical study described in the Examples section below.
• Fig. 5 is a graph showing the mean improvement in EASI score observed in the clinical study described in the Examples section below.
• Fig. 6 is a graph showing the percent of subjects achieving EASI-75 in the clinical study described in the Examples section below.
• Fig. 7 is a graph comparing the percent of subjects achieving EASI-75 score observed in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 8 is a graph showing the mean improvement in SCORAD observed in the clinical study described in the Examples section below.
• Fig. 9 is a graph comparing the mean improvement in SCORAD observed in the clinical study described in the Examples section below between the 200 mg and 400 mg groups.
• Fig. 10 is a graph comparing the percent improvement in SCORAD observed in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 11 is a graph showing the mean improvement in GISS observed in the clinical study described in the Examples section below.
• Fig. 12 is a graph comparing the percent improvement in GISS observed in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 13 is a graph showing the percent of subjects achieving at least a 2 point reduction in IGA in the clinical study described in the Examples section below.
• Fig. 14 is a graph comparing the percent of subject achieving at least a 4 point reduction in IGA and a final IGA score of 0 or 1 in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 15 is a graph showing the mean improvement in DLQI score observed in the clinical study described in the Examples section below.
• Fig. 16 is a graph comparing the mean point reduction in DLQI for subjects in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 17 is a graph showing the mean improvement in POEM score observed in the clinical study described in the Examples section below.
• Fig. 18 is a graph comparing the mean improvement in POEM score observed at 4 weeks in the clinical study described in the Examples section below between the 200 mg and 400 mg groups.
• Fig. 19 is a graph showing the mean point reduction in POEM score for subjects in the clinical study described in the Examples section below.
• Fig. 20 is a graph comparing the mean point reduction in POEM score for subjects in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 21 is a graph showing the mean improvement in HADS score for anxiety and depression observed in the clinical study described in the Examples section below.
• Fig. 22 is a graph showing the mean point reduction in HADS depression score for subjects in the clinical study described in the Examples section below.
• Fig. 23 is a graph showing the mean point reduction in HADS combined score for subjects in the clinical study described in the Examples section below.
• Fig. 24 is a graph comparing the mean point reduction in HADS combined score for subjects in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 25 is a graph showing the percent of subjects achieving at least a 4 point reduction in NRS Worst Itch score observed in the clinical study described in the Examples section below.
• Fig. 26 is a graph showing the percent of subjects achieving at least a 4 point reduction in NRS Overall Itch score observed in the clinical study described in the Examples section below.
• Fig. 27 is a graph comparing the percent of subjects achieving at least a 4 point reduction in week 4 NRS Worst Itch score observed in the clinical study described in the Examples section below versus data published for dupilumab.
• Fig. 28 is a graph showing the percent of subjects achieving at least a 4 point reduction in NRS Pain score observed in the clinical study described in the Examples section below.
• compositions and methods for reducing a symptom of AD in a subject are described herein.
• the below described preferred embodiments illustrate adaptation of these compositions and methods. Nonetheless, from the description of these embodiments, other aspects of the invention can be made and/or practiced based on the description provided below.
• compositions and methods described herein are useful for treating a symptom of AD (e.g., erythema, excoriation, papulation, infiltration, lichenification, itching, pain, oozing, crusting, swelling, bleeding, scratch marks, flaking, and sleep loss).
• a symptom of AD e.g., erythema, excoriation, papulation, infiltration, lichenification, itching, pain, oozing, crusting, swelling, bleeding, scratch marks, flaking, and sleep loss.
• Successful treatment of AD can be evaluated according to established assays known in the art.
• a reduction in a symptom of AD includes a reduction of at least 8 points in a patient’s EASI score, a reduction of at least 1 point in a patient’s IGA score; a reduction of at least 2 points in a patient’ s NRS score (itch or pain); a reduction of at least 10 points in a patient’s SCORAD score; a reduction of at least 3 points in a patient’s POEM score; and a reduction of at least 2 points in a patient’s total GISS score.
• the mammalian subject might be any that suffers from AD including, human beings.
• Human subjects might be male, female, adults, children, seniors (65 and older), and those with other diseases.
• Particularly preferred subjects are those whose disease has progressed or failed to respond after treatment with other anti-inflammatory agents such as topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, dupilumab, nemolizumab, and phototherapy.
• Subjects who have developed a human anti-human antibody response due to prior administration of therapeutic antibodies are preferred when the anti-IL-loc Ab is a true human Ab (e.g., one with all V regions naturally expressed in a human subject) such as bermekimab (MABpl).
• MABpl bermekimab
• any suitable type of Ab that specifically binds IL-loc and reduces a characteristic of AD in a subject might be used in the methods described herein.
• the anti-IL-la Ab used might be mAh, a polyclonal Ab, a mixture of mAbs, or an Ab fragment or engineered Ab-like molecule such as an scFv.
• the Ka of the Ab is preferably at least 1 xlO 9 M 1 or greater (e.g., greater than 9 xlO 10 M 1 , 8 xlO 10 M 1 , 7 xlO 10 M 1 , 6 xlO 10 M 1 , 5 xlO 10 M 1 , 4 xlO 10 M 1 , 3 xlO 10 M 1 , 2 xlO 10 M 1 , or 1 xlO 10 M 1 ).
• the Ab is a fully human mAh that includes (i) an antigen-binding variable region that exhibits very high binding affinity (e.g., at least nano or picomolar) for human IL-loc and (ii) a constant region.
• the human Ab is preferably an IgGl, although it might be of a different isotype such as IgM, IgA, or IgE, or subclass such as IgG2, IgG3, or IgG4.
• IgGl is bermekimab (MABpl), an IL- loc-specific IgGl mAh described in U.S. patent number 8,034,337.
• mAbs are those that include at least one but preferably all the CDRs of bermekimab, those that neutralize IL-loc (e.g., those that prevent IL-loc from binding an IL- la receptor), and those that compete for binding to IL-la with bermekimab (e.g., by competition ligand-receptor interaction assay).
• B lymphocytes which express Ig specific for human IL-la occur naturally in human beings
• a presently preferred method for raising mAbs is to first isolate such a B lymphocyte from a subject and then immortalize it so that it can be continuously replicated in culture.
• Subjects lacking large numbers of naturally occurring B lymphocytes which express Ig specific for human IL-la may be immunized with one or more human IL-la antigens to increase the number of such B lymphocytes.
• Human mAbs are prepared by immortalizing a human Ab secreting cell (e.g., a human plasma cell). See, e.g., U.S. patent no. 4,634,664.
• one or more human subjects are screened for the presence of such human IL-la-specific Ab in their blood.
• Those subjects that express the desired Ab can then be used as B lymphocyte donors.
• peripheral blood is obtained from a human donor that possesses B lymphocytes that express human IL-la-specific Ab.
• B lymphocytes are then isolated from the blood sample, e.g., by cells sorting (e.g., fluorescence activated cell sorting,“FACS”; or magnetic bead cell sorting) to select B lymphocytes expressing human IL-la-specific Ig.
• cells sorting e.g., fluorescence activated cell sorting,“FACS”; or magnetic bead cell sorting
• the B lymphocytes within this population that express Ig specific for human IL-la can then be isolated by limiting dilution methods (e.g., cells in wells of a microtiter plate that are positive for Ig specific for human IL-la are selected and subcultured, and the process repeated until a desired clonal line can be isolated). See, e.g., Goding, MAbs: Principles and Practice, pp. 59-103, Academic Press, 1986.
• Those clonal cell lines that express Ig having at least nanomolar or picomolar binding affinities for human IL- la are preferred.
• MAbs secreted by these clonal cell lines can be purified from the culture medium or a bodily fluid (e.g., ascites) by conventional Ig purification procedures such as salt cuts, size exclusion, ion exchange separation, and affinity chromatography.
• Ig purification procedures such as salt cuts, size exclusion, ion exchange separation, and affinity chromatography.
• immortalized B lymphocytes might be used in in vitro cultures to directly produce mAbs, in certain cases it might be desirable to use heterologous expression systems to produce mAbs. See, e.g., the methods described in U.S. patent application number 11/754,899.
• the genes encoding an mAh specific for human IL-la might be cloned and introduced into an expression vector (e.g., a plasmid-based expression vector) for expression in a heterologous host cell (e.g., CHO cells, COS cells, myeloma cells, and E. coli cells).
• an expression vector e.g., a plasmid-based expression vector
• a heterologous host cell e.g., CHO cells, COS cells, myeloma cells, and E. coli cells.
• Igs include heavy (H) and light (L) chains in an H2L2 configuration
• the genes encoding each may be separately isolated and expressed in different vectors.
• chimeric mAbs e.g., “humanized” mAbs
• Such chimeric Abs can be prepared by methods known in the art. See, e.g., Morrison et ah, Proc. Nat'l. Acad. Sci.
• Abs can be humanized by methods known in the art.
• mAbs with a desired binding specificity can be humanized by various vendors or as described in U.S. Pat. Nos. 5,693,762; 5,530, 101; or 5,585,089.
• the mAbs described herein might be affinity matured to enhance or otherwise alter their binding specificity by known methods such as VH and VL domain shuffling (Marks et al. Bio/Technology 10:779-783, 1992), random mutagenesis of the hypervariable regions (HVRs) and/or framework residues (Barbas et al. Proc Nat. Acad. Sci. USA 91 :3809-3813, 1994; Schier et al. Gene 169: 147-155, 1995; Yelton et al. J. Immunol. 155: 1994-2004, 1995; Jackson et al., J. Immunol. 154(7):3310-9, 1995; and Hawkins et al, J. Mol.
• Amino acid sequence variants of an Ab may be prepared by introducing appropriate changes into the nucleotide sequence encoding the Ab.
• modifications to nucleic acid sequences encoding mAbs might be altered (e.g., without changing the amino acid sequence of the mAh) for enhancing production of the mAh in certain expression systems (e.g., intron elimination and/or codon optimization for a given expression system).
• the mAbs described herein can also be modified by conjugation to another protein (e.g., another mAh) or non-protein molecule.
• a mAh might be conjugated to a water soluble polymer such as polyethylene glycol or a carbon nanotube (See, e.g., Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605, 2005). See, U.S. patent application number 11/754,899.
• a water soluble polymer such as polyethylene glycol or a carbon nanotube
• the mAh compositions should be at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.9 or more percent by weight pure (excluding any excipients).
• the mAh compositions might include only a single type of mAh (i.e., one produced from a single clonal B lymphocyte line) or might include a mixture of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different types of mAbs.
• IL-loc specific Abs described above are preferred for use in the methods described herein, in some cases, other agents that specifically target IL-loc might be used so long as their administration leads to improvement of a characteristic AD. Because bermekimab has been shown to block the action of IL-loc by preventing its interaction with the IL-1 receptor (IL- 1R1), based on this mechanism of action in treating AD, other Abs or non-Ab agents that also block IL-1 a from interacting with IL-1R1 could also be used to reduce a symptom of AD (e.g., other anti-IL-la Abs or anti-IL-lRl Abs which block IL-loc from interacting with IL-1R1). These Abs can be made according to the methods described above.
• Non-Ab agents might include vaccines that cause the production of anti-IL-la Abs which block IL-la from interacting with IL- 1R1, proteins or peptides that bind IL-la and block IL-la from interacting with IL-1R1, and small organic molecules which specifically target IL-la and block IL-la from interacting with IL- 1R1. Those that do not specifically bind other agents that specifically target IL-Ib are preferred. Whether a particular agent is able to treat one or more symptoms of AD in a subject can be determined by the methods described in the Examples section below and those that are known in the art.
• the anti-IL-loc Ab compositions may be administered to animals or humans in pharmaceutically acceptable carriers (e.g., sterile saline), that are selected on the basis of mode and route of administration and standard pharmaceutical practice.
• pharmaceutically acceptable carriers e.g., sterile saline
• a list of pharmaceutically acceptable carriers, as well as pharmaceutical formulations, can be found in Remington’ s Pharmaceutical Sciences, a standard text in this field, and in USP/NF.
• Other substances may be added to the compositions and other steps taken to stabilize and/or preserve the compositions, and/or to facilitate their administration to a subject.
• the Ab compositions might be lyophilized (see Draber et al., J. Immunol. Methods. 181 :37, 1995; and PCT/US90/01383); dissolved in a solution including sodium and chloride ions; dissolved in a solution including one or more stabilizing agents such as albumin, glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine; filtered (e.g., using a 0.45 and/or 0.2 micron filter); contacted with beta-propiolactone; and/or dissolved in a solution including a microbicide (e.g., a detergent, an organic solvent, and a mixture of a detergent and organic solvent.
• a microbicide e.g., a detergent, an organic solvent, and a mixture of a detergent and organic solvent.
• the Ab compositions may be administered to animals or humans by any suitable technique. Typically, such administration will be parenteral (e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal introduction).
• the compositions may also be administered directly to the target site (e.g., the skin) by, for example, topical application.
• Other methods of delivery e.g., liposomal delivery or diffusion from a device impregnated with the composition, are known in the art.
• the composition may be administered in a single bolus, multiple injections, or by continuous infusion (e.g., intravenously or by peritoneal dialysis).
• a therapeutically effective amount is an amount which is capable of producing a medically desirable result in a treated animal or human.
• An effective amount of anti-IL-la Ab compositions is an amount which shows clinical efficacy in patients as measured by the improvement in one or more symptoms of AD.
• dosage for any one animal or human depends on many factors, including the subject’s size, body surface area, age, the particular composition to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
• Preferred doses range from about 3 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22) mg/kg body weight.
• a single dose may be effective at resolving a symptom of AD.
• doses may be given repeatedly, e.g., semi-weekly, weekly, bi-weekly, tri-weekly, semi-monthly, once every three weeks, monthly, bi-monthly, or as needed (if the symptom of AD recurs or to prevent recurrence of AD symptoms once resolved).
• the mAbs described herein as well as other mAbs can include about 180, 200, 220, 240, 260, 280, 300, or more mAh per ml of the pharmaceutical composition, and/or can be formulated as a liquid composition that have a viscosity of at least about 20 cP (centipoise) at 25°C (e.g., at least 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 cP at 25°C).
• cP centipoise
• the isoelectric points (pi) of such antibodies can be about 6, 6.5., 7, 7.5, 8, 8.5, 9, 9.5, or 10 (e.g., as determined by imaged capillary isoelectric focusing).
• mAbs include those that target TNF-a, IL-Ib, IL-2, IL-4, IL-5, IL- 6, IL-12, IL-13, IL-17A, IL-22, IL-31, IL-33, IFN-g, and GM-CSF.
• mAbs also include: Examples of antibodies include, without limitation, Infliximab, Bevacizumab, Ranibizumab, Cetuximab, Ranibizumab, Palivizumab, Abagovomab, Abciximab, Actoxumab, Adalimumab, Afelimomab, Afutuzumab, Alacizumab, Alacizumab pegol, ALD518, Alemtuzumab, Alirocumab, Alemtuzumab, Altumomab, Amatuximab, Anatumomab mafenatox, Anrukinzumab, Apolizumab, Arcitumomab, Aselizumab, Altinumab, Atlizumab, Atorolimiumab, tocilizumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Belim
• Romosozumab Rontalizumab, Rovelizumab, Ruplizumab, Samalizumab, Sarilumab, Satumomab pendetide, Secukinumab, Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomab paptox, Tefibazumab, Telimomab aritox, Tenatumomab, Tefibazumab, Telimomab aritox, Tenat
• Vesencumab Visilizumab, Volociximab, Vorsetuzumab mafodotin, Votumumab, Zalutumumab, Zanolimumab, Zatuximab, Ziralimumab and Zolimomab aritox.
• Example 1 Open label study of subcutaneous bermekimab (MABpl) administration in two dose cohorts for moderate to severe atopic dermatitis.
• BSA body surface area
• Immunosuppressive/immunomodulating drugs eg, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, IFN-g, Janus kinase inhibitors, azathioprine, methotrexate, etc.
• TCS topical corticosteroids
• TCI topical calcineurin inhibitors
• HIV human immunodeficiency virus
• hepatitis B surface antigen (HBsAg) or hepatitis C antibody • Positive with hepatitis B surface antigen (HBsAg) or hepatitis C antibody at the screening visit
• examples include, but are not limited to, patients with short life expectancy, patients with uncontrolled diabetes (HbAlc > 9%), patients with cardiovascular conditions (eg, stage III or IV cardiac failure according to the New York Heart Association classification), severe renal conditions (eg, patients on dialysis), hepatobiliary conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active major autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary or lymphatic diseases.
• the specific justification for patients excluded under this criterion will be noted in study documents (chart notes, case report forms [CRFs], etc.)
• One dosage form is a sterile liquid formulation of 100 mg/mL bermekimab in a stabilizing isotonic subcutaneous formulation buffer at pH 6.2-6.5.
• Each 2-mL Type I borosilicate glass serum vial contains 2 mL of the formulation and is sealed with a 13-mm Daikyo Flurotec butyl rubber stopper and flip-off aluminum seal.
• the exact composition of the Drug Product is shown in Table 1 below.
• the other dosage form used is a sterile liquid formulation of 200 mg/mL bermekimab in a stabilizing isotonic subcutaneous formulation buffer at pH 6.2-6.5. See Table 2 below.
• the drug product is packaged in pre-filled syringes.
• the pre-filled syringes used are OMPI EZ-Fill Nexa, 2.25mL 27G 1 ⁇ 2 needle, or a comparable alternative.
• the barrel of the syringe is clear glass borosilicate type 1 with AISI 304 stainless steel thin wall needle containing 2mL of the formulation and is sealed with West l-3mL Novapure piston (plunger) with Flurotec coating.
• composition Drug Product [200mg/mL]
• the dose of bermekimab for Group A is 200 mg (2ml of the 100 mg/ml formulation) and for Group B is 400 mg (2ml of the 200 mg/ml formulation) administered weekly by subcutaneous injection.
• the study is multicenter, and consists of two dose levels: bermekimab administered subcutaneously at a dose of 200 mg weekly (4 doses) and bermekimab administered subcutaneously at a dose of 400 mg weekly (8 doses).
• Patients taking the 200mg dose are followed for 5 weeks (6 visits, day 35 +/- 2), and patients taking the 400mg dose are followed for 8 weeks (9 visits, day 56 +1-2) to allow for assessment of safety and efficacy.
• the study calendar is shown in Fig.
• a Chemistry Panel including: Albumin, Alkaline Phosphatase, ALT, AST, GGT, Bicarbonate (C02) Calcium, Chloride, Creatinine, Glucose, Potassium, Sodium, Total Bilirubin, Total Protein, Urea Nitrogen.
• b Hematology Panel including: Complete whole blood (WBC, HgB, Platelet, differential).
• d Data from patient diary for the previous 7 days to be recorded at this time.
• e Interferon gamma release assay. fBMI will be calculated at this visit using height and weight.
• Urinalysis will assess pH, protein, glucose, and blood cells.
• Vital signs include blood pressure, pulse, oxygen saturation, respiratory rate and body temperature.
• EASI Eczema Area and Severity Index Score
• IGA Investigator's Global Assessment
• PK Pharmacokinetics
• SCORAD Change in SCORing Atopic Dermatitis
• SCORAD index a measure of disease severity in AD. It includes assessment of the eczema in addition to patient reported symptoms. Total score ranges from 0 to 103 (no disease to most severe disease, respectively).
• POEM Patient Oriented Eczema Measure
• Atopic dermatitis is characterized by chronic inflammation of the skin, which results in a breakdown of the skin barrier and leads to dry, thickened, scaly skin, redness, and itching, the latter which can be debilitating and result in significant sleep disturbances and loss of quality of life.
• a survey of persons suffering from atopic dermatitis found that 91% of patients endured itching every day (Dawn et al. Itch characteristics in atopic dermatitis: results of a web-based questionnaire. Br J Dermatol. 2009; 160(3):642-644), and another study reported that 36% of patients feel that their primary treatment objective is to reduce itch (Schmitt et al.
• EASI Another key measure of efficacy in the study was the EASI.
• the two dose groups received weekly subcutaneous injections using XBiotech’s recently developed pre-filled syringes that contain a concentrated formula of bermekimab. Improvement was assessed from baseline to the endpoint, which was either 4 or 7 weeks from start of treatment. Significant improvements were indicated by all aforementioned measures for the high dose group.
• Example 2 Formulation of an anti-IL-la mAh with improved bioavailability.
• the estimated bioavailability is 61% for 200 mg dose group, but 94% for 400 mg dose group.
• the 400 mg dose group used a newly developed formulation of 200 mg/mL, while the 200 mg dose group used the formulation of 100 mg/mL.
• This new formulation of 200 mg/mL is observed to have higher viscosity (38.2 cP measured at 25°C).
• the higher viscosity though, may help with the resistance to fluid flow through the interstitium who already has high viscosity due to tight association of water to hyaluronic acid.
• the lymphatic capillaries are blind-ended and composed of a single layer of overlapping endothelial cells, and lack tight cell cell junctions as well as a continuous basement membrane.
• Increase in interstitial pressure stretches the fibers and leads to an opening of lymphatic lumen, which allows easy entry of large- molecular-weight solutes.
• the increase in viscosity and drug concentration in the new formulation may result in the increase of interstitial pressure and make the new formulation easier to be absorbed into a lymphatic system.
• the faster absorption of 400 mg dose group is confirmed with the observation that a steady state of plasma concentration is achieved after only two treatment cycles, as the accumulation starting from cycle three is not more than 4% for each cycle. On the other hand, in the 200 mg dose group, the steady state is barely achieved at the end of the study (the fourth treatment cycle).

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