Immunology and Immunotoxicity of Nanomedicines

Transcription

1 Immunlgy and Immuntxicity f Nanmedicines Jacques DESCOTES, MD, PharmD, PhD, fellw ATS Prfessr and Head, Pisn Center and Pharmacvigilance Department Lyn University Hspitals, Lyn, France = jacques-gerges.desctes@chu-lyn.fr

2 Intrductin Nanmedicines ptentially useful t diagnse r treat a variety f pathlgical cnditins: imaging nantls, diagnstic nanchips and nansensrs, nandelivery systems fr vaccines, therapeutic prteins/peptides and antibdies, targeted nantherapeutics Widely hetergeneus grup f mlecular entities: dendrimers, fullerenes, quantum dts, nantubes, nanspheres, nanhrns, nanshells, lipsmes with highly variable physicchemical characteristics including size, shape, surface area and reactivity One cnsistent feature: "ne r mre dimensins f the rder f 100 nm r less" Marked txiclgical as well as immuntxiclgical hetergeneity t be expected acrss nanmedicines

3 Immunlgy f nanmedicines Nanparticles, and presumably nanmedicines as well, can: interact with immune cells, such as macrphages, mncytes, dendritic cells, lymphcytes trigger nn-specific inflammatry respnses via generatin f active xygen species (xidative burst) and release f pr-inflammatry cytkines (TNF-α, IL-1, IL-6, IL-18 ) activate the cmplement cascade, and the platelets facilitate antigen-specific hypersensitivity reactins via interactins with T lymphcytes and release f chemkines and immunregulatry cytkines (IFN-γ, IL-2, IL-8, GM-CSF ) Hwever, sme nanparticles can als: suppress inflammatry respnses exert n immunmdulatry prperties

4 Immunlgy f nanmedicines As f tday: n cmprehensive data available n the immunlgical effects f nanparticles and nanmedicines n clear understanding n the exquisite mechanisms invlved t accunt fr widely differing immunlgical effects Imprtantly: immunlgical effects immuntxicity immuntxicity evaluatin as part f a regulatry prcess study f immunlgical effects useful primarily: t identify pssible causes fr cncern t be addressed during dedicated immuntxicity evaluatin t prvide mechanistic clues n reprted immuntxic effects

5 Immuntxic ptential f nanmedicines Immunsuppressin Immunstimulatin/immunactivatin Hypersensitivity Aut-immunity

6 Immunsuppressin Adverse clinical cnsequences: mre frequent and mst ften severe bacterial, viral, fungal and/r parasitic infectins due t impaired resistance t pathgens mre frequent virus-assciated neplasias, e.g. skin cancers and lymphmas Immunsuppressive nanparticles/nanmedicines rather rarely described s far: multiwalled carbn nantubes ply(d,l-lactide-c-glyclide) (PLGA) particles plyhydrxy C60 (water-sluble fullerene derivative) chlesterylbutyrate-cnjugated lipid nanparticles

7 Immunsuppressin Nanparticles/nanmedicines may prve t be immunsuppressive due t: targeted r nandelivery engineering t btain intended immunsuppressive agents r frmulatins sequestratin within lymphid rgans r tissues, f variable duratin, pssibly resulting in immunsuppressive effects, e.g. thrugh inhibitin f phagcytsis, r immune cell functins (macrphages) inadvertent immunsuppressive effects always pssible

8 Immunsuppressin Preclinical evaluatin: regulatry setting current lack f dedicated guideline strategy adapted frm ICH S8 r ISO TS (medical devices) guidelines? shrt-term ( 28-day) repeat-dse txicity study assessment based n clinical signs, standard hematlgy/clinical chemistry, and histlgy f main lymphid rgans weight f evidence apprach at least ne immune functin assay (TDAR) deemed t be abslutely essential due t currently pr knwledge n immuntxicity ptential f nanmedicines pitfalls related t cnsistency and quality f nanmedicines assumed t be vercme prir t cnducting dedicated immuntxicity study

9 Immunsuppressin Preclinical evaluatin: shrtcmings and pending issues additinal immune functin assays (in vitr r ex viv) deemed t be mst ften necessary based n knwn r suspected immunlgical effects f tested nanmedicine: e.g. macrphage functin, cmplement activatin currently available (in vitr r ex viv) assays prly standardized and validated, particularly as regards safety evaluatin f nanparticles and nanmedicines imprtantly, s far n in vitr assay as yet shwn t be reliable predictr f immunsuppressive ptential fr the time being, in vitr and ex viv assays cnsidered t be useful nly case by case t address pssible causes f cncern, e.g. cnsequences f prlnged sequestratin in macrphages r suspected cmplement activatin effrts t design, standardize and validate reliable (in vitr r ex viv) assays urgently needed

10 Immunstimulatin/immunactivatin Adverse clinical cnsequences: inflammatry cmplicatins due t cytkine release and/r cmplement activatin ("flu-like" reactins, acute cytkine syndrmes) mre frequent autimmune diseases mre frequent hypersensitivity reactins tward unrelated allergens IL-6 mediated inhibitin f CYP450 pathways Nanparticles may be immunstimulatry/activating current develpment f immune nanadjuvants fr vaccines r nanimmuntherapeutic agents cytkine release induced by many nanparticles enhanced sensitizatin t valbumin thrugh inhalatin f ultrafine diesel r thilated chitsan nanparticles (decreased sensitizatin als pssible! e.g. inhalatin f fullerenes)

11 Immunstimulatin/immunactivatin Preclinical evaluatin: regulatry setting: n dedicated guideline shrt-term (28-day) repeat-dse txicity study same design as assessment f immunsuppressive ptential ptentially helpful? ex viv r in vitr assays fcused n pssible adverse effects cytkine release assays using human cell lines r human bld cmplement activatin, lymphcyte prliferatin standardizatin and validatin t nanmedicines urgently needed safety immunpharmaclgy studies? selected case by case t address causes fr cncern e.g. rdent mdels f allergen-induced asthma r IgE-dependent anaphylaxis

12 Hypersensitivity Adverse clinical cnsequences: immune-mediated hypersensitivity reactins anaphylaxis, immun-allergic cytpenias, T-cell mediated rganspecific hypersensitivity reactins (pneumnitis, hepatitis, nephritis ), smetimes life-threatening seemingly nt reprted s far nnimmune-mediated (pseud-allergic) hypersensitivity reactins direct (nn-specific) histamine release r cmplement activatin (resulting in generatin f the anaphylatxins C3a and C5a, and frmatin f the membrane attack cmplex C5b-9) n prir sensitizing cntact required (pssible first-dse reactin) smewhat different clinically frm IgE-dependent anaphylaxis

13 Hypersensitivity Cncern regarding immune-mediated hypersensitivity related t: pssible intrinsic immungenicity f nanmlecules (but lw mlecular weight and nn-peptidic structure) immungenicity f nanmlecules resulting frm inadvertently adsrbed chemicals r purpsely bund chemicals r drug miety (targeted engineering) Cncern regarding nnimmune-mediated hypersensitivity related t: pseud-allergic reactins thrugh cmplement activatin reprted with lipsmes (and Cremphr El )

14 Hypersensitivity Preclinical evaluatin: regulatry setting: n dedicated guideline preclinical assessment suspected t be less tricky than with therapeutic prteins lack f humanizatin f current nanmedicines (animal mdels theretically applicable) lack f metablic activatin (n invlvement f reactive metablites) predictin still hampered by many limitatins and pitfalls mdels and assays selected case by case

15 Hypersensitivity Preclinical evaluatin: mdels and assays systemic r cutaneus passive anaphylaxis t detect specific IgE in previusly treated rdents r guinea-pigs basphil activatin assay (flw cytmetry), pssible with human bld samples histamine release assay, als pssible with human bld samples cmplement activatin: ex viv r in viv measurement f anaphylatxins (C3a, C5a), C3adesarg, r SC5b-9 frm human bld samples dedicated pig and dg mdels f lipsme-induced cmplement activatin (rdents relatively insensitive)

16 Autimmunity Autimmunity can manifest as systemic (e.g. lupus) r rgan-specific (e.g. myasthenia) disease Only elusive data available n pssible link between autimmunity and expsure t ultrafine particles Autimmunity ptential beynd reach f any reliable predictin t date

17 Cnclusin Currently available immunlgical data deemed t suggest immuntxicity ptential as an (at least theretical) cause fr cncern with mst, if nt all nanmedicines systematic preclinical immuntxicity evaluatin t be recmmended Mst current mdels and assays presumably applicable t sme extent even thugh standardizatin and adaptatin t nanmedicines evaluatin bviusly needed Specificities and mdalities f the immuntxicity evaluatin f nanmedicines t be identified and validated fr regulatry purpse