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Биологическая терапия меланомы
Биологическая терапия меланомы
Кравченко А.С. Биологическая терапия меланомы. Consilium Medicum. 2020; 22 (7): 29–32. DOI: 10.26442/20751753.2020.7.200297
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Аннотация
Меланома – злокачественная опухоль кожи, характеризующаяся высокой распространенностью как в Российской Федерации, так и во всем мире, быстрым ростом, способностью к локальному и отдаленному метастазированию и высокой летальностью. Открытие и внедрение моноклональных антител позволило достичь определенных успехов в лечении ряда заболеваний, в том числе меланомы. Высокая эффективность использования моноклональных антител достигается за счет их точно направленного действия на определенные молекулы, что позволило увеличить общую выживаемость пациентов со злокачественными новообразованиями. В качестве терапии меланомы высокую эффективность продемонстрировали ингибиторы иммунных контрольных точек (CTLA-4 и PD-1), такие как ипилимумаб, ниволумаб и пембролизумаб. Эффективность данных моноклональных антител подтверждена в исследованиях, где они назначались в качестве монотерапии и комбинированной терапии, и выражалась в увеличении общей выживаемости пациентов с меланомой кожи. Однако терапия моноклональными антителами может быть связана с риском возникновения побочных реакций. Целью данного обзора является обобщение современных данных о биологической терапии меланомы.
Ключевые слова: биологическая терапия, меланома, моноклональные антитела.
Key words: biological therapy, melanoma, monoclonal antibodies.
Ключевые слова: биологическая терапия, меланома, моноклональные антитела.
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Key words: biological therapy, melanoma, monoclonal antibodies.
Полный текст
Список литературы
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[Melanoma kozhi i slizistykh obolochek. Klinicheskie rekomendatsii. 2018 (in Russian).]
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[Malishevskaia N.P., Sokolova A.V., Demidov L.V. Sovremennoe sostoianie zabolevaemosti melanomoi kozhi. Med. sovet. 2018; 10: 161–5 (in Russian).]
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[Kabanova M.A. Epidemiologicheskaia situatsiia po zabolevaemosti melanomoi v Rossii v 2015 godu. Sovremennye problemy zdravookhraneniia i meditsinskoi statistiki. 2017; 3: 23–36 (in Russian).]
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[Kaneva P.L., Mil'chakov D.E. Sravnitel'naia kharakteristika zabolevaemosti melanomoi v nekotorykh sub"ektakh Privolzhskogo federal'nogo okruga. Mezhdunar. nauchno-issledovatel'skii zhurn. 2015; 2 (33): 38–9 (in Russian).]
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25. Hodi FS, O‘Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (8): 711–23.
26. Sharpe AH. Mechanisms of costimulation. Immunol Rev 2009; 229 (1): 5–11.
27. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002; 16 (1): 23–35.
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29. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 2017; 7 (1): e1364828–e1364828.
30. Kil SH, Estephan R, Sanchez J et al. PD-L1 is regulated by interferon gamma and interleukin 6 through STAT1 and STAT3 signaling in cutaneous T-cell lymphoma. Blood 2017; 130 (Suppl. 1): 1458.
31. Przepiorka D, Ko CW, Deisseroth A et al. FDA approval: blinatumomab. Clin Cancer Res 2015; 21 (18): 4035–9.
32. Wan MT, Ming ME. Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal. Br J Dermatol 2018; 179 (2): 296–300.
33. Rogiers A, Boekhout A, Schwarze JK et al. Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors. J Oncol 2019: 5269062.
34. Amaral T, Seeber O, Mersi E et al. Primary Resistance to PD-1-Based Immunotherapy – A Study in 319 Patients with Stage IV Melanoma. Cancers 2020; 12 (4): 1027.
35. Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28 (19): 3167–75.
36. Schadendorf D, Hodi FS, Robert C et al. Pooled Analysis of Long-Term Survival Data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33 (17): 1889–94.
37. Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372 (26): 2521–32.
38. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372 (4): 320–30.
39. Hodi FS, Chiarion-Sileni V, Gonzalez R et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19: 1480–92.
40. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Abstract CT075: Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients with advanced melanoma (CheckMate 067). Cancer Res 2017; 77 (Suppl. 13): CT075.
41. Long GV, Atkinson V, Menzies AM et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). 2017; Abstract 9508.
2. Garbe С, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016. Eur J Cancer 2016; 63: 201–17.
3. Malishevskaia N.P., Sokolova A.V., Demidov L.V. Sovremennoe sostoianie zabolevaemosti melanomoi kozhi. Med. sovet. 2018; 10: 161–5 (in Russian).
4. Kabanova M.A. Epidemiologicheskaia situatsiia po zabolevaemosti melanomoi v Rossii v 2015 godu. Sovremennye problemy zdravookhraneniia i meditsinskoi statistiki. 2017; 3: 23–36 (in Russian).
5. Kaneva P.L., Mil'chakov D.E. Sravnitel'naia kharakteristika zabolevaemosti melanomoi v nekotorykh sub"ektakh Privolzhskogo federal'nogo okruga. Mezhdunar. nauchno-issledovatel'skii zhurn. 2015; 2 (33): 38–9 (in Russian).
6. Haurum JS. Recombinant polyclonal antibodies: the next generation of antibody therapeutics? Drug Discov Today 2006; 11: 655–60.
7. McDermott D, Lebbe C, Hodi FS et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treatment Rev 2014; 40 (9): 1056–64.
8. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol 2010; 10: 345–52.
9. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 2010; 9: 767–74.
10. Masami S, Chie K, Atsuhiko Kato. Concise Review Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. J Toxicol Pathol 2015; 28: 133–9.
11. Foltz IN, Karow M, Wasserman SM. Evolution and Emergence of Therapeutic Monoclonal Antibodies. Circulation 2013; 127: 2222–30.
12. Daeron M. Fc receptor biology. Annu Rev Immunol 1997; 15: 203–34.
13. Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel) 2019; 8 (4): 55.
14. Kolar GR, Capra DJ. Immunoglobulins: structure and function. In: Paul WE, ed. Fundamental Immunology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
15. Janda A, Bowen A, Greenspan NS, Casadevall A. Ig Constant Region Effects on Variable Region Structure and Function. Front Microbiol 2016; 7: 1–10.
16. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010; 49: 493–507.
17. Brunton L, Chabner BA, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth. McGraw-Hill Education/Medical; 12 edition (16 Feb. 2011).
18. Katzung B, Masters SB, Trevor AJ. Basic and Clinical Pharmacology, 11th Edition (Lange Basic Science). McGraw-Hill Medical; 11 edition (1 Aug. 2009).
19. Tang P, Liang S, Xu J et al. Screening of Monoclonal Antibodies for Cancer Treatment. J Clin Exp Oncol 2018; 7: 4.
20. Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer 2007; 109 (2): 170–9.
21. Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res Basel Karger 2014; 41.
22. Reslan L, Dalle S, Dumontet C. Understanding and circumventing resistance to anticancer monoclonal antibodies. MAbs 2009; 1 (3): 222–9.
23. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271 (5256): 1734–6.
24. Pons-Tostivint E, Latouche A, Vaflard P et al. Comparative analysis of durable responses on immune checkpoint inhibitors versus other systemic therapies: a pooled analysis of phase III trials. JCO Precis Oncol 2019; 3: 1–10.
25. Hodi FS, O‘Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (8): 711–23.
26. Sharpe AH. Mechanisms of costimulation. Immunol Rev 2009; 229 (1): 5–11.
27. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002; 16 (1): 23–35.
28. Du X, Tang F, Liu M et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018; 28 (4): 416–32.
29. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 2017; 7 (1): e1364828–e1364828.
30. Kil SH, Estephan R, Sanchez J et al. PD-L1 is regulated by interferon gamma and interleukin 6 through STAT1 and STAT3 signaling in cutaneous T-cell lymphoma. Blood 2017; 130 (Suppl. 1): 1458.
31. Przepiorka D, Ko CW, Deisseroth A et al. FDA approval: blinatumomab. Clin Cancer Res 2015; 21 (18): 4035–9.
32. Wan MT, Ming ME. Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal. Br J Dermatol 2018; 179 (2): 296–300.
33. Rogiers A, Boekhout A, Schwarze JK et al. Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors. J Oncol 2019: 5269062.
34. Amaral T, Seeber O, Mersi E et al. Primary Resistance to PD-1-Based Immunotherapy – A Study in 319 Patients with Stage IV Melanoma. Cancers 2020; 12 (4): 1027.
35. Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28 (19): 3167–75.
36. Schadendorf D, Hodi FS, Robert C et al. Pooled Analysis of Long-Term Survival Data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33 (17): 1889–94.
37. Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372 (26): 2521–32.
38. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372 (4): 320–30.
39. Hodi FS, Chiarion-Sileni V, Gonzalez R et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19: 1480–92.
40. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Abstract CT075: Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients with advanced melanoma (CheckMate 067). Cancer Res 2017; 77 (Suppl. 13): CT075.
41. Long GV, Atkinson V, Menzies AM et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). 2017; Abstract 9508.
[Melanoma kozhi i slizistykh obolochek. Klinicheskie rekomendatsii. 2018 (in Russian).]
2. Garbe С, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016. Eur J Cancer 2016; 63: 201–17.
3. Малишевская Н.П., Соколова А.В., Демидов Л.В. Современное состояние заболеваемости меланомой кожи. Мед. совет. 2018; 10: 161–5.
[Malishevskaia N.P., Sokolova A.V., Demidov L.V. Sovremennoe sostoianie zabolevaemosti melanomoi kozhi. Med. sovet. 2018; 10: 161–5 (in Russian).]
4. Кабанова М.А. Эпидемиологическая ситуация по заболеваемости меланомой в России в 2015 году. Современные проблемы здравоохранения и медицинской статистики. 2017; 3: 23–36.
[Kabanova M.A. Epidemiologicheskaia situatsiia po zabolevaemosti melanomoi v Rossii v 2015 godu. Sovremennye problemy zdravookhraneniia i meditsinskoi statistiki. 2017; 3: 23–36 (in Russian).]
5. Канева П.Л., Мильчаков Д.Е. Сравнительная характеристика заболеваемости меланомой в некоторых субъектах Приволжского федерального округа. Междунар. научно-исследовательский журн. 2015; 2 (33): 38–9.
[Kaneva P.L., Mil'chakov D.E. Sravnitel'naia kharakteristika zabolevaemosti melanomoi v nekotorykh sub"ektakh Privolzhskogo federal'nogo okruga. Mezhdunar. nauchno-issledovatel'skii zhurn. 2015; 2 (33): 38–9 (in Russian).]
6. Haurum JS. Recombinant polyclonal antibodies: the next generation of antibody therapeutics? Drug Discov Today 2006; 11: 655–60.
7. McDermott D, Lebbe C, Hodi FS et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treatment Rev 2014; 40 (9): 1056–64.
8. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol 2010; 10: 345–52.
9. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 2010; 9: 767–74.
10. Masami S, Chie K, Atsuhiko Kato. Concise Review Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. J Toxicol Pathol 2015; 28: 133–9.
11. Foltz IN, Karow M, Wasserman SM. Evolution and Emergence of Therapeutic Monoclonal Antibodies. Circulation 2013; 127: 2222–30.
12. Daeron M. Fc receptor biology. Annu Rev Immunol 1997; 15: 203–34.
13. Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel) 2019; 8 (4): 55.
14. Kolar GR, Capra DJ. Immunoglobulins: structure and function. In: Paul WE, ed. Fundamental Immunology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
15. Janda A, Bowen A, Greenspan NS, Casadevall A. Ig Constant Region Effects on Variable Region Structure and Function. Front Microbiol 2016; 7: 1–10.
16. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010; 49: 493–507.
17. Brunton L, Chabner BA, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth. McGraw-Hill Education/Medical; 12 edition (16 Feb. 2011).
18. Katzung B, Masters SB, Trevor AJ. Basic and Clinical Pharmacology, 11th Edition (Lange Basic Science). McGraw-Hill Medical; 11 edition (1 Aug. 2009).
19. Tang P, Liang S, Xu J et al. Screening of Monoclonal Antibodies for Cancer Treatment. J Clin Exp Oncol 2018; 7: 4.
20. Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer 2007; 109 (2): 170–9.
21. Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res Basel Karger 2014; 41.
22. Reslan L, Dalle S, Dumontet C. Understanding and circumventing resistance to anticancer monoclonal antibodies. MAbs 2009; 1 (3): 222–9.
23. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271 (5256): 1734–6.
24. Pons-Tostivint E, Latouche A, Vaflard P et al. Comparative analysis of durable responses on immune checkpoint inhibitors versus other systemic therapies: a pooled analysis of phase III trials. JCO Precis Oncol 2019; 3: 1–10.
25. Hodi FS, O‘Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (8): 711–23.
26. Sharpe AH. Mechanisms of costimulation. Immunol Rev 2009; 229 (1): 5–11.
27. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002; 16 (1): 23–35.
28. Du X, Tang F, Liu M et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018; 28 (4): 416–32.
29. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 2017; 7 (1): e1364828–e1364828.
30. Kil SH, Estephan R, Sanchez J et al. PD-L1 is regulated by interferon gamma and interleukin 6 through STAT1 and STAT3 signaling in cutaneous T-cell lymphoma. Blood 2017; 130 (Suppl. 1): 1458.
31. Przepiorka D, Ko CW, Deisseroth A et al. FDA approval: blinatumomab. Clin Cancer Res 2015; 21 (18): 4035–9.
32. Wan MT, Ming ME. Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal. Br J Dermatol 2018; 179 (2): 296–300.
33. Rogiers A, Boekhout A, Schwarze JK et al. Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors. J Oncol 2019: 5269062.
34. Amaral T, Seeber O, Mersi E et al. Primary Resistance to PD-1-Based Immunotherapy – A Study in 319 Patients with Stage IV Melanoma. Cancers 2020; 12 (4): 1027.
35. Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28 (19): 3167–75.
36. Schadendorf D, Hodi FS, Robert C et al. Pooled Analysis of Long-Term Survival Data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33 (17): 1889–94.
37. Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372 (26): 2521–32.
38. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372 (4): 320–30.
39. Hodi FS, Chiarion-Sileni V, Gonzalez R et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19: 1480–92.
40. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Abstract CT075: Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients with advanced melanoma (CheckMate 067). Cancer Res 2017; 77 (Suppl. 13): CT075.
41. Long GV, Atkinson V, Menzies AM et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). 2017; Abstract 9508.
________________________________________________
2. Garbe С, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016. Eur J Cancer 2016; 63: 201–17.
3. Malishevskaia N.P., Sokolova A.V., Demidov L.V. Sovremennoe sostoianie zabolevaemosti melanomoi kozhi. Med. sovet. 2018; 10: 161–5 (in Russian).
4. Kabanova M.A. Epidemiologicheskaia situatsiia po zabolevaemosti melanomoi v Rossii v 2015 godu. Sovremennye problemy zdravookhraneniia i meditsinskoi statistiki. 2017; 3: 23–36 (in Russian).
5. Kaneva P.L., Mil'chakov D.E. Sravnitel'naia kharakteristika zabolevaemosti melanomoi v nekotorykh sub"ektakh Privolzhskogo federal'nogo okruga. Mezhdunar. nauchno-issledovatel'skii zhurn. 2015; 2 (33): 38–9 (in Russian).
6. Haurum JS. Recombinant polyclonal antibodies: the next generation of antibody therapeutics? Drug Discov Today 2006; 11: 655–60.
7. McDermott D, Lebbe C, Hodi FS et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treatment Rev 2014; 40 (9): 1056–64.
8. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol 2010; 10: 345–52.
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Авторы
А.С. Кравченко*
ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*agrevtseva@mail.ru
Russian Medical Academy of Continuous Professional Education, Moscow, Russia
agrevtseva@mail.ru
ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*agrevtseva@mail.ru
________________________________________________
Russian Medical Academy of Continuous Professional Education, Moscow, Russia
agrevtseva@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.