Monoclonal antibody-based therapies for microbial diseases

Carolyn Saylor, Ekaterina Dadachova, Arturo Casadevall, Carolyn Saylor, Ekaterina Dadachova, Arturo Casadevall

Abstract

The monoclonal antibody (mAb) revolution that currently provides many new options for the treatment of neoplastic and inflammatory diseases has largely bypassed the field of infectious diseases. Only one mAb is licensed for use against an infectious disease, although there are many in various stages of development. This situation is peculiar given that serum therapy was one of the first effective treatments for microbial diseases and that specific antibodies have numerous antimicrobial properties. The underdevelopment and underutilization of mAb therapies for microbial diseases has various complex explanations that include the current availability of antimicrobial drugs, small markets, high costs and microbial antigenic variation. However, there are signs that the climate for mAb therapeutics in infectious diseases is changing given increasing antibiotic drug resistance, the emergence of new pathogenic microbes for which no therapy is available, and development of mAb cocktail formulations. Currently, the major hurdle for the widespread introduction of mAb therapies for microbial diseases is economic, given the high costs of immunoglobulin preparations and relatively small markets. Despite these obstacles there are numerous opportunities for mAb development against microbial diseases and the development of radioimmunotherapy provides new options for enhancing the magic bullet. Hence, there is cautious optimism that the years ahead will see more mAbs in clinical use against microbial diseases.

References

    1. Wu H., Pfarr D.S., Losonsky G.A., Kiener P.A. Immunoprophylaxis of RSV infection: advancing from RSV-IGIV to palivizumab and motavizumab. Curr Top Microbiol Immunol. 2008;317:103–123.
    1. Casadevall A. The third age of antimicrobial therapy. Clin Infect Dis. 2006;42(May (10)):1414–1416.
    1. Casadevall A., Scharff M.D. Serum therapy revisited: animal models of infection and development of passive antibody therapy. Antimicrob Agents Chemother. 1994;38(August (8)):1695–1702.
    1. Casadevall A., Scharff M.D. Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis. 1995;21(July (1)):150–161.
    1. Casadevall A. The case for pathogen-specific therapy. Expert Opin Pharmacother. 2009;10(12):1–5.
    1. Casadevall A., Dadachova E., Pirofski L.A. Passive antibody therapy for infectious diseases. Nat Rev Microbiol. 2004;2(September 9):695–703.
    1. Buchwald U.K., Pirofski L. Immune therapy for infectious diseases at the dawn of the 21st century: the past, present and future role of antibody therapy, therapeutic vaccination and biological response modifiers. Curr Pharm Des. 2003;9(12):945–968.
    1. ter Meulen J. Monoclonal antibodies for prophylaxis and therapy of infectious diseases. Expert Opin Emerg Drugs. 2007;12(November (4)):525–540.
    1. Brock, T.D. (Ed.), Milestones in Microbiology: 1556 to 1940. ASM Press, 1998.
    1. Doherty M., Robertson M.J. Some early trends in immunology. Trends Immunol. 2004;25(December (12)):623–631.
    1. Casadevall A. Passive antibody therapies: progress and continuing challenges. Clin Immunol. 1999;93(October (1)):5–15.
    1. Keller M.A., Stiehm E.R. Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev. 2000;13(October (4)):602–614.
    1. Velicer C.M., Heckbert S.R., Lampe J.W., Potter J.D., Robertson C.A., Taplin S.H. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291(February (7)):827–835.
    1. Kozyrskyj A.L., Ernst P., Becker A.B. Increased risk of childhood asthma from antibiotic use in early life. Chest. 2007;131(June (6)):1753–1759.
    1. Lang A.B., Cryz S.J., Jr., Schurch U., Ganss M.T., Bruderer U. Immunotherapy with human monoclonal antibodies. Fragment A specificity of polyclonal and monoclonal antibodies is crucial for full protection against tetanus toxin. J Immunol. 1993;151(July (1)):466–472.
    1. Pachl J., Svoboda P., Jacobs F., Vandewoude K., van der Hoven B., Spronk P. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis. 2006;42(May (10)):1404–1413.
    1. Akiyama M., Oishi K., Tao M., Matsumoto K., Pollack M. Antibacterial properties of Pseudomonas aeruginosa immunotype 1 lipopolysaccharide-specific monoclonal antibody (MAb) in a murine thigh infection model: combined effects of MAb and ceftazidime. Microbiol Immunol. 2000;44(8):629–635.
    1. Devi S.J. Preclinical efficacy of a glucuronoxylomannan-tetanus toxoid conjugate vaccine of Cryptococcus neoformans in a murine model. Vaccine. 1996;14(June (9)):841–844.
    1. Han Y., Ulrich M.A., Cutler J.E. Candida albicans mannan extract-protein conjugates induce a protective immune response against experimental candidiasis. J Infect Dis. 1999;179(June (6)):1477–1484.
    1. Pedraz C., Carbonell-Estrany X., Figueras-Aloy J., Quero J. Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus hospitalizations in premature infants. Pediatr Infect Dis J. 2003;22(September (9)):823–827.
    1. McKeating J.A., Gow J., Goudsmit J., Pearl L.H., Mulder C., Weiss R.A. Characterization of HIV-1 neutralization escape mutants. AIDS. 1989;3(December (12)):777–784.
    1. Keck Z.Y., Li S.H., Xia J., von Hahn T., Balfe P., McKeating J.A. Mutations in hepatitis C virus E2 located outside the CD81 binding sites lead to escape from broadly neutralizing antibodies but compromise virus infectivity. J Virol. 2009;83(June (12)):6149–6160.
    1. Zharikova D., Mozdzanowska K., Feng J., Zhang M., Gerhard W. Influenza type A virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2. J Virol. 2005;79(June (11)):6644–6654.
    1. Prabakaran M., Prabhu N., He F., Hongliang Q., Ho H.T., Qiang J. Combination therapy using chimeric monoclonal antibodies protects mice from lethal H5N1 infection and prevents formation of escape mutants. PLoS ONE. 2009;4(5):e5672.
    1. ter Meulen J., van den Brink E.N., Poon L.L., Marissen W.E., Leung C.S., Cox F. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006;3(July (7)):e237.
    1. Seiler P., Senn B.M., Brundler M.A., Zinkernagel R.M., Hengartner H., Kalinke U. In vivo selection of neutralization-resistant virus variants but no evidence of B cell tolerance in lymphocytic choriomeningitis virus carrier mice expressing a transgenic virus-neutralizing antibody. J Immunol. 1999;162(April (8)):4536–4541.
    1. Bakker A.B., Python C., Kissling C.J., Pandya P., Marissen W.E., Brink M.F. First administration to humans of a monoclonal antibody cocktail against rabies virus: safety, tolerability, and neutralizing activity. Vaccine. 2008;26(November (47)):5922–5927.
    1. Chames P., Van Regenmortel M., Weiss E., Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol. 2009;157(May (2)):220–233.
    1. Maggon K. Monoclonal antibody “gold rush”. Curr Med Chem. 2007;14(18):1978–1987.
    1. LaRocca T.J., Katona L.I., Thanassi D.G., Benach J.L. Bactericidal action of a complement-independent antibody against relapsing fever Borrelia resides in its variable region. J Immunol. 2008;180(May (9)):6222–6228.
    1. Martin-Mateos M.A. Monoclonal antibodies in pediatrics: use in prevention and treatment. Allergol Immunopathol (Madr) 2007;35(July–August (4)):145–150.
    1. Raff H.V., Siscoe P.J., Wolff E.A., Maloney G., Shuford W. Human monoclonal antibodies to group B streptococcus. Reactivity and in vivo protection against multiple serotypes. J Exp Med. 1988;168(September (3)):905–917.
    1. Casadevall A., Pirofski L.A. A reappraisal of humoral immunity based on mechanisms of antibody-mediated protection against intracellular pathogens. Adv Immunol. 2006;91:1–44.
    1. Marasco W.A., Sui J. The growth and potential of human antiviral monoclonal antibody therapeutics. Nat Biotechnol. 2007;25(December (12)):1421–1434.
    1. Olson W.C., Jacobson J.M. CCR5 monoclonal antibodies for HIV-1 therapy. Curr Opin HIV AIDS. 2009;4(March (2)):104–111.
    1. Perez L.G., Costa M.R., Todd C.A., Haynes B.F., Montefiori D.C. Utilization of IgG Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane proximal external region of gp41. J Virol. 2009;83(August (15)):7397–7410.
    1. Blish C.A., Jalalian-Lechak Z., Rainwater S., Nguyen M.A., Dogan O.C., Overbaugh J. Cross-subtype neutralization sensitivity despite monoclonal antibody resistance among early subtype A, C, and D HIV-1 envelope variants. J Virol. 2009;83(August (15)):7783–7788.
    1. Sato S., Johnson W. Antibody-mediated neutralization and simian immunodeficiency virus models of HIV/AIDS. Curr HIV Res. 2007;5(November (6)):594–607.
    1. Song L., Sun Z.Y., Coleman K.E., Zwick M.B., Gach J.S., Wang J.H. Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface. Proc Natl Acad Sci USA. 2009;106(June (22)):9057–9062.
    1. Hessell A.J., Rakasz E.G., Poignard P., Hangartner L., Landucci G., Forthal D.N. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 2009;5(May (5)):e1000433.
    1. Pantophlet R., Wrin T., Cavacini L.A., Robinson J.E., Burton D.R. Neutralizing activity of antibodies to the V3 loop region of HIV-1 gp120 relative to their epitope fine specificity. Virology. 2008;381(November (2)):251–260.
    1. Cainelli F., Vent S. Infections and solid organ transplant rejection: a cause-and-effect relationship? Lancet Infect Dis. 2002;2(September (9)):539–549.
    1. Radziewicz H., Hanson H.L., Ahmed R., Grakoui A. Unraveling the role of PD-1/PD-L interactions in persistent hepatotropic infections: potential for therapeutic application? Gastroenterology. 2008;134(June (7)):2168–2171.
    1. Martinez O., Tsibane T., Basler C.F. Neutralizing anti-influenza virus monoclonal antibodies: therapeutics and tools for discovery. Int Rev Immunol. 2009;28(1):69–92.
    1. Ascione A., Capecchi B., Campitelli L., Imperiale V., Michela F., Zamboni S. Human monoclonal antibodies in single chain fragment variable format with potent neutralization activity against influenza virus H5N1. Antiviral Res. 2009;83(September (3)):238–244.
    1. Yoshida R., Igarashi M., Ozaki H., Kishida N., Tomabechi D., Kida H. Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog. 2009;5(March (3)):e1000350.
    1. Throsby M., van den Brink E., Jongeneelen M., Poon L.L., Alard P., Cornelissen L. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE. 2008;3(12):e3942.
    1. Ekiert D.C., Bhabha G., Elsliger M.A., Friesen R.H., Jongeneelen M., Throsby M. Antibody recognition of a highly conserved influenza virus epitope. Science. 2009;324(April (5924)):246–251.
    1. Chen J., Deng Y.M. Influenza virus antigenic variation, host antibody production and new approach to control epidemics. Virol J. 2009;6:30.
    1. Roehrig J.T., Staudinger L.A., Hunt A.R., Mathews J.H., Blair C.D. Antibody prophylaxis and therapy for flavivirus encephalitis infections. Ann N Y Acad Sci. 2001;December (951):286–297.
    1. Ben-Nathan D., Gershoni-Yahalom O., Samina I., Khinich Y., Nur I., Laub O. Using high titer West Nile intravenous immunoglobulin from selected Israeli donors for treatment of West Nile virus infection. BMC Infect Dis. 2009;9:18.
    1. Diamond M.S. Progress on the development of therapeutics against West Nile Virus. Antiviral Res. 2009;83(September (3)):214–227.
    1. Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(November (6965)):450–454.
    1. Xiao X., Chakraborti S., Dimitrov A.S., Gramatikoff K., Dimitrov D.S. The SARS-CoV S glycoprotein: expression and functional characterization. Biochem Biophys Res Commun. 2003;312(December (4)):1159–1164.
    1. Sui J., Li W., Murakami A., Tamin A., Matthews L.J., Wong S.K. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci USA. 2004;101(February (8)):2536–2541.
    1. Prabakaran P., Zhu Z., Xiao X., Biragyn A., Dimitrov A.S., Broder C.C. Potent human monoclonal antibodies against SARS CoV, Nipah and Hendra viruses. Expert Opin Biol Ther. 2009;9(March (3)):355–368.
    1. Zhu Z., Dimitrov A.S., Bossart K.N., Crameri G., Bishop K.A., Choudhry V. Potent neutralization of Hendra and Nipah viruses by human monoclonal antibodies. J Virol. 2006;80(January (2)):891–899.
    1. Serna At, Boedeker E.C. Pathogenesis and treatment of Shiga toxin-producing Escherichia coli infections. Curr Opin Gastroenterol. 2008;24(January (1)):38–47.
    1. Zhang Q., Donohue-Rolfe A., Krautz-Peterson G., Sevo M., Parry N., Abeijon C. Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J Infect Dis. 2009;199(February (4)):486–493.
    1. Bitzan M., Poole R., Mehran M., Sicard E., Brockus C., Thuning-Roberson C. Safety and pharmacokinetics of chimeric anti-shiga toxin 1 and anti-shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrob Agents ChemotherV 53. 2009;(July (7)):3081–3087.
    1. Bitzan M. Treatment options for HUS secondary to Escherichia coli O157:H7. Kidney Int Suppl. 2009;(February (112)):S62–S66.
    1. Ma Y., Mao X., Li J., Li H., Feng Y., Chen H. Engineering an anti-Stx2 antibody to control severe infections of EHEC O157:H7. Immunol Lett. 2008;121(December (2)):110–115.
    1. Leffler D.A., Lamont J.T. Treatment of Clostridium difficile-associated disease. Gastroenterology. 2009;136(May (6)):1899–1912.
    1. Dubberke E.R., Wertheimer A.I. Review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30(January (1)):57–66.
    1. Miller A.T., Tabrizian P., Greenstein A.J., Dikman A., Byrn J., Divino C. Long-term follow-up of patients with fulminant Clostridium difficile colitis. J Gastrointest Surg. 2009;13(May (5)):956–959.
    1. He X., Sun X., Wang J., Wang X., Zhang Q., Tzipori S. Antibody-enhanced, Fc gamma receptor-mediated endocytosis of Clostridium difficile toxin A. Infect Immun. 2009;77(June (6)):2294–2303.
    1. Nagy E., Giefing C., von Gabain A. Anti-infective antibodies: a novel tool to prevent and treat nosocomial diseases. Expert Rev Anti Infect Ther. 2008;6(February (1)):21–30.
    1. Weisman L.E., Fischer G.W., Thackray H.M., Johnson K.E., Schuman R.F., Mandy G.T. Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults. Int Immunopharmacol. 2009;9(May (5)):639–644.
    1. Weisman L.E. Antibody for the prevention of neonatal noscocomial staphylococcal infection: a review of the literature. Arch Pediatr. 2007;14(September (Suppl. 1)):S31–S34.
    1. Weisman L.E. Coagulase-negative staphylococcal disease: emerging therapies for the neonatal and pediatric patient. Curr Opin Infect Dis. 2004;17(June (3)):237–241.
    1. John J.F., Jr. Drug evaluation: tefibazumab—a monoclonal antibody against staphylococcal infection. Curr Opin Mol Ther. 2006;8(October (5)):455–460.
    1. Ragle B.E., Bubeck Wardenburg J. Anti-{alpha}-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect Immun. 2009 (Oct 5, Epub ahead of print)
    1. Casadevall A. Passive antibody administration (immediate immunity) as a specific defense against biological weapons. Emerg Infect Dis. 2002;8(August (8)):833–841.
    1. Schneemann A., Manchester M. Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax. Future Microbiol. 2009;February (4):35–43.
    1. Kulkeaw K., Sakolvaree Y., Srimanote P., Tongtawe P., Maneewatch S., Sookrung N. Human monoclonal ScFv neutralize lethal Thai cobra, Naja kaouthia, neurotoxin. J Proteom. 2009;72(March (2)):270–282.
    1. Larsen R.A., Pappas P.G., Perfect J., Aberg J.A., Casadevall A., Cloud G.A. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother. 2005;49(March (3)):952–958.
    1. Rachini A., Pietrella D., Lupo P., Torosantucci A., Chiani P., Bromuro C. An anti-beta-glucan monoclonal antibody inhibits growth and capsule formation of Cryptococcus neoformans in vitro and exerts therapeutic, anticryptococcal activity in vivo. Infect Immun. 2007;75(November (11)):5085–5094.
    1. Torosantucci A., Bromuro C., Chiani P., De Bernardis F., Berti F., Galli C. A novel glyco-conjugate vaccine against fungal pathogens. J Exp Med. 2005;202(September (5)):597–606.
    1. Magliani W., Conti S., Giovati L., Maffei D.L., Polonelli L. Anti-beta-glucan-like immunoprotective candidacidal antiidiotypic antibodies. Front Biosci. 2008;13:6920–6937.
    1. Pincus S.H., Fang H., Wilkinson R.A., Marcotte T.K., Robinson J.E., Olson W.C. In vivo efficacy of anti-glycoprotein 41, but not anti-glycoprotein 120, immunotoxins in a mouse model of HIV infection. J Immunol. 2003;170(February (4)):2236–2241.
    1. Order S.E., Stillwagon G.B., Klein J.L., Leichner P.K., Siegelman S.S., Fishman E.K. Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. J Clin Oncol. 1985;3(December (12)):1573–1582.
    1. Milenic D.E., Brady E.D., Brechbiel M.W. Antibody-targeted radiation cancer therapy. Nat Rev Drug Discov. 2004;3(June (6)):488–499.
    1. Sharkey R.M., Goldenberg D.M. Perspectives on cancer therapy with radiolabeled monoclonal antibodies. J Nucl Med. 2005;46(January (Suppl. 1)):115S–127S.
    1. Kaminski M.S., Tuck M., Estes J., Kolstad A., Ross C.W., Zasadny K. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005;352(February (5)):441–449.
    1. Dadachova E., Nakouzi A., Bryan R.A., Casadevall A. Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection. Proc Natl Acad Sci USA. 2003;100(September (19)):10942–10947.
    1. Dadachova E., Howell R.W., Bryan R.A., Frenkel A., Nosanchuk J.D., Casadevall A. Susceptibility of the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum to gamma-radiation versus radioimmunotherapy with alpha- and beta-emitting radioisotopes. J Nucl Med. 2004;45(February (2)):313–320.
    1. Martinez L.R., Bryan R.A., Apostolidis C., Morgenstern A., Casadevall A., Dadachova E. Antibody-guided alpha radiation effectively damages fungal biofilms. Antimicrob Agents Chemother. 2006;50(June (6)):2132–2136.
    1. Dadachova E., Burns T., Bryan R.A., Apostolidis C., Brechbiel M.W., Nosanchuk J.D. Feasibility of radioimmunotherapy of experimental pneumococcal infection. Antimicrob Agents Chemother. 2004;48(May (5)):1624–1629.
    1. Dadachova E., Patel M.C., Toussi S., Apostolidis C., Morgenstern A., Brechbiel M.W. Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins. PLoS Med. 2006;3(November (11)):e427.
    1. Dadachova E., Bryan R.A., Frenkel A., Zhang T., Apostolidis C., Nosanchuk J.S. Evaluation of acute hematologic and long-term pulmonary toxicities of radioimmunotherapy of Cryptococcus neoformans infection in murine models. Antimicrob Agents Chemother. 2004;48(March (3)):1004–1006.
    1. Retallack D.M., Woods J.P. Molecular epidemiology, pathogenesis, and genetics of the dimorphic fungus Histoplasma capsulatum. Microbes Infect. 1999;1(August (10)):817–825.
    1. Nosanchuk J.D., Steenbergen J.N., Shi L., Deepe G.S., Jr., Casadevall A. Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum. J Clin Invest. 2003;112(October (8)):1164–1175.
    1. Little S.J., Holte S., Routy J.P., Daar E.S., Markowitz M., Collier A.C. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347(August (6)):385–394.
    1. Dadachova E., Casadevall A. Antibodies as delivery vehicles for radioimmunotherapy of infectious diseases. Expert Opin Drug Deliv. 2005;2(November (6)):1075–1084.
    1. Dadachova E., Nosanchuk J.D., Shi L., Schweitzer A.D., Frenkel A., Nosanchuk J.S. Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin. Proc Natl Acad Sci USA. 2004;101(October (41)):14865–14870.
    1. Kaufmann G.F., Park J., Janda K.D. Bacterial quorum sensing: a new target for anti-infective immunotherapy. Expert Opin Biol Ther. 2008;8(June (6)):719–724.
    1. Pai J.C., Sutherland J.N., Maynard J.A. Progress towards recombinant anti-infective antibodies. Recent Pat Antiinfect Drug Discov. 2009;4(January (1)):1–17.
    1. Wigfield S.M., Rigg G.P., Kavari M., Webb A.K., Matthews R.C., Burnie J.P. Identification of an immunodominant drug efflux pump in Burkholderia cepacia. J Antimicrob Chemother. 2002;49(April (4)):619–624.
    1. Presta L. Evolving an anti-toxin antibody. Nat Biotechnol. 2007;25(January (1)):63–65.
    1. Beck A., Wagner-Rousset E., Bussat M.C., Lokteff M., Klinguer-Hamour C., Haeuw J.F. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol. 2008;9(December (6)):482–501.
    1. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov. 2009;8(March (3)):226–234.
    1. Chen W., Dimitrov D.S. Human monoclonal antibodies and engineered antibody domains as HIV-1 entry inhibitors. Curr Opin HIV AIDS. 2009;4(March (2)):112–117.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj