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What Is the Target Group for Antitoxin Treatment to Prevent Clostridioides

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What Is the Target Group for Antitoxin Treatment to Prevent Clostridioides What is the target group for antitoxin treatment to prevent Clostridioides difficile infection? Dr Tanya M Monaghan Clinical Associate Professor & Honorary Consultant Gastroenterologist NIHR Nottingham Digestive Diseases Biomedical Research Centre University of Nottingham, UK ESCMID eLibrary © by author Transparency declaration • I am a Consultant advisor to CHAIN Biotechnology • I co-supervise a BBSRC iCASE DTP PhD-funded student with industrial partner CHAIN Biotechnology ESCMID eLibrary © by author Presentation overview • Toxins in disease pathogenesis • Antitoxin strategies • Role of humoral immunity in host defence • Evidence review • Likely place in therapy • Unanswered questions and future considerations ESCMID eLibrary © by author Structure of C. difficile toxins A (TcdA) and B (TcdB) AktoriesESCMIDK et al 2017 Annu. Rev. Microbiol 71; 281-307 eLibrary © by author Toxin-induced CDI pathogenesis ESCMID eLibraryAktories K et al 2017 Annu. Rev. Microbiol 71; 281-307 © by author ChandrasekaranESCMIDR at al 2017 FEMS Microbial Rev; 41: 723 -750eLibrary © by author Antitoxin antibody-mediated therapies for C. difficile infection Passive immunotherapies Active immunotherapies/toxin- • Systemic: based vaccines • Humanised antitoxin mAbs • Systemic: • Polyclonal IVIg • PF-06425090 (Pfizer; phase III) • Genetically and chemically detoxified • Oral TcdA and TcdB • IgAbulin • VLA84 (Valneva; phase II) • Hyperimmune bovine Ig • Recombinant chimeric protein concentrate linking binding domains of TcdA and • Mucomilk (polyclonal-antibody TcdB enriched whey protein concentrate) ESCMID eLibrary © by author Small molecule inhibitors of toxin domains *Compounds found to be active against TcdA and TcdB ESCMID eLibraryGarland M et al 2017 Chem Rev; 117: 4422-4461 © by author 2013 2000 Circulating Ab and memory 1994 1983 High serum IgG antitoxin A associates B-cell responses Higher serum IgG Detection of antitoxin antibodies in with asymptomatic carriage anti-toxin A and sera of healthy and infected subjects faecal IgA anti- 2015 2001 toxin A in single v Detection of isotype specific Low serum IgG antitoxin A associates with relapsing CDI antitoxin Abs by microarray higher risk of rCDI 1992 Systemic and mucosal Ab 1995 2016 response to toxin A in patients Selective Detection of serum with CDI neutralization 2007 antitoxin IgG by of toxin A by 2006 Low IgG2 and IgG3 electrochemiluminescence IgA IVIg for Rx of subclass responses 1991 severe, to toxin A in rCDI IVIg for chronic relapsing C. 2016 refractory difficile colitis Bezlotoxumab rCDI ELISA Protein Microarray ESCMID eLibraryElectrochemiluminescence © by author 1 = acute; 2 = convalescent; 3 = asymptomatic CD excretors; 4 = healthy controls NB: No correlation between binding and neutralising anti-toxin A antibody levels and ESCMIDresolution of symptoms (JohnsoneLibrary S et al 1992 JID 166; 1287-94) © by author Warny M et al 1994 Infect Immun; 62: 384-389 72% adults and 40% children < 2 yrs have detectable IgG to toxin A Non-immunocompromised patients (grey) Serum IgG antitoxin A levels increase ↑ serum and faecal antibody levels than with age in healthy controls; ↑ in men cytostatic-treated patients (black) and c/w women > 60 yrs ESCMID eLibrarycontrols (white) © by author Relation of antibody levels to presence of relapse ESCMID eLibraryWarny M et al 1994 Infect Immun; 62: 384-389 © by author Recurrent CDI associates with: • Low day 3 IgM anti-toxin A; OR 9 (95% CI 1.6-49.4) • Low serum IgG antitoxin A Low serum IgG anti- (<1.29 EU) at toxin A levels (< 3.00 EU) day 12; OR 48 associate with ↑risk of (95% CI 3.5- developing CDI; OR 48; 663) (95% CI, 3.4-678; P <0.001)) ESCMIDKyne L eteLibrary al NEJM 2000; 342: 390-7 and Lancet 2001; 357: 189-93 © by author Monaghan et al PLoS One 2013; 8 (9) e74452 Circulating C. difficile toxin A-specific, antigen-activated memory B cells by flow cytometry n=16 (39 blood samples collected median 181 (81- 415) days after CDI onset) [0.82 (0-4.93) % vs 0.33 (0-2.12) %] Toxin A- and B-specific ASC frequencies in patients with CDI by ESCMID eLibraryELISpot © by author Critical evidence review • Heterogeneity in study populations and methodologies • Lack of concordance with binding and neutralising titres • Presence of neutralising antitoxin antibody activity independent of clinical response • Role of non-neutralising antitoxin antibodies has not been defined • Longitudinal surveys assessing dynamics of response often missing • Poor understanding of memory B cell response • Mucosal immunity often not assessed – reliance on circulating responses ESCMID• Phenotypic variation in antibody response eLibrary often not explored © by author IVIg therapy for severe C. difficile colitis • IVIg induces clinical resolution in 2 patients with severe PMC not responding to SOC metronidazole and vancomycin • IgG antitoxin A and B antibodies are readily detected in IVIg preparations • C. difficile toxin neutralising activity evident at IgG concentrations of 0.4- 1.6mg/mL SalcedoESCMID et al 1997 Gut; 41: 366-370 eLibrary © by author (a)Immune reactivity of multi- isotype specific antibodies to C. difficile toxin and non-toxin antigens in 3 commercial IVIg preparations by protein microarray. Total IgG, IgG1 and IgG2 isotypes give highest binding reactivities against toxin A, toxin B and binary toxin (pCDTb) (b) IVIg neutralisation efficacy against C. difficile native whole toxins A and B NegmESCMID OH et al 2017 Clin Exp Immunol; 188: 437-443 eLibrary © by author (a)Antibody reactivities against C. difficile antigens in patient sera pre- and post IVIg (b)Serum IgG responses to toxins A, B and binary toxin (pCDTb) pre and post-IVIg (c)Neutralisation activity against C. difficile toxins A and B pre- and post-IVIg ESCMID eLibrary © by author IVIg – place in therapy • IDSA/SHEA 2017 guidelines: • IVIg can be used at concentration of 150-400 mg/kg, in patients with fulminant CDI not responding to vancomycin and metronidazole • Lack of randomised control trials • Lack of consensus regarding optimal dosing, timing of administration and type of commerical IVIg • World Society of Emergency Surgery (WSES) 2019 guidelines • IVIg should only be used as adjunct therapy in patients with multiple recurrent or fulminant CDI until results from large RCTs are available • Public Health England: • Severe (or recurrent) CDI is considered an appropriate use of IVIg ESCMID eLibrary © by author Preclinical development and subsequent testing of neutralising fully human monoclonal antibodies directed against C. difficile toxins A & B 2006: Anti-toxin A HuMAb, actoxumab (MK-3415, GS- CDA1, or MDX-066) and anti-toxin B HuMAb, bezlotoxumab (MK-6072, MBL-CDB1, or MDX-1388) subsequently taken forward ESCMID eLibrary © by author Both actoxumab and bezlotoxumab are IgG1 monoclonals and map to putative receptor binding domains of respective toxins Bezlotoxumab binds to 2 separate sites within the N- terminal half of combined repetitive oligopeptide (CROP) domain to toxin B, partially occluding 2 of 4 putative carbohydrate binding pockets for the toxins (Orth P et al 2014 J Biol Chem; 26: 18008-18021) Similar mechanism of protection for actoxumab (Hernandez LD et al 2017 J Mol Biol; 429: 1030-44) Bezlotoxumab prevents toxin B interaction with host receptor chondroitin sulfate proteoglycan (CSPG4) Model of the TcdB CROP domain bound (Gupta P et al 2017 J Biol Chem; 292: 17290-301) to full-length molecule of ESCMIDbezlotoxumab eLibrary © by author Toxin-directed HuMAbs protect hamsters Babcock et al 2006 Infect Immun; 74: 6339-6347 PRMARY CHALLENGE MODEL RELAPSE MODEL CDA1: 50mg/kg/day (4 days) CDA1: 60mg/kg/day (4 days) ESCMIDMDX1388: 10-50 mg/kg/day) eLibraryMDX1388: 20 mg/kg/day) © by author Toxin-directed HuMAbs protect mice in C. difficile Mechanisms of protection challenge models Prevention of damage and inflammation in gut wall in ileal loop and spore challenge models Mutant forms of antibodies that do not bind to Mouse model of systemic Fcγ receptors also provide protection, toxin challenge suggesting MOP is direct neutralisation via Intra-gastric spore F(ab’)2 regions and does not involve host challenge model effector functions (prophylactic and Normalisation of gut microbiota (reduction in therapeutic paradigms of Enterobacter and restoration of core primary CDI) components of original microbiota, Blautia, Mouse model of recurrent Akkermansia, and Lactobacillus) C. difficile infection Yang Z et al 2015; Infect Immun; 83: 822-831 ESCMIDDzunkova M et al 2016; Front Cell Infect Microbiol; 6:119 eLibrary © by author Phase 2 trials Subjects randomized in double-blind fashion to IV CDA1/actoxumab (10mg/kg) or placebo while on SOC treatment for CDI • Results: • 29 subjects received actoxumab; 17 subjects placebo • CDI recurrence similar in actoxumab and placebo arms (5/29 [17%] and 3/17 [18%]; P = NS) during 56-day follow up • Predictors of recurrence • Lower neutralising anti-toxin B antibodies at day 14 • Lower anti-toxin A neutralising antibodies at day 28 • Infection with epidemic BI/NAP1/027 strain ESCMIDLeav BA et al 2010 Vaccine; 28: 965-9 eLibrary © by author Phase 2 trials ESCMID eLibrary © by author Phase 2 trial evidence for toxin-directed HuMabs Randomised, double-blind, placebo-controlled study • Active comparator: HuMabs against C. difficile toxins A (CDA1/actoxumab) and B (CDB1/bezlotoxumab) administered as single infusion (10 mg/kg) vs placebo (0.9% saline) • Patients > 18 yrs with symptomatic infection who were receiving SOC (either metro/vanc) • 30 sites in US and Canada •
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