Beyond Recycling Antibodies: Crovalimab’s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment
Abstract
:1. Introduction
2. Results
2.1. Creation Journey of Crovalimab and Key Antibody Engineering
2.2. Engineered IgG1 Constant Region of Crovalimab
2.3. FcγR and C1q Binding Properties of Crovalimab
2.4. C5 Binding Characteristics of Crovalimab
2.5. Effect of pH Dependency and Surface-Charge Engineering on C5 Clearance
2.6. Efficiency of C5 Inhibition by Crovalimab
2.7. Viscosity Potential of Crovalimab
3. Discussion
4. Materials and Methods
4.1. Preparation of C5, FcγRs, and Antibodies
4.2. FcγR Binding Assay
4.3. C1q Binding Assay
4.4. C5 Binding Kinetics Analysis by Surface Plasmon Resonance
4.5. Neutralizing Activity of Anti-C5 Antibodies
4.6. Structure Modeling
4.7. Simulation of Effect of C5–Antibody Complex Clearance on C5 Accumulation
4.8. In Vivo Study Using Human FcRn Transgenic Mice
4.9. CIEX Analysis
4.10. Viscosity Assessment
4.11. Quantification of Efficiency of C5 Neutralization
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Devos, T.; Meers, S.; Boeckx, N.; Gothot, A.; Deeren, D.; Chatelain, B.; Chatelain, C.; Devalet, B. Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel. Eur. J. Haematol. 2018, 101, 737–749. [Google Scholar] [CrossRef] [PubMed]
- Hillmen, P. The role of complement inhibition in PNH. Hematology 2008, 2008, 116–123. [Google Scholar] [CrossRef] [PubMed]
- Richards, S.J.; Painter, D.; Dickinson, A.J.; Griffin, M.; Munir, T.; Arnold, L.; Payne, D.; Pike, A.; Muus, P.; Hill, A.; et al. The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK’s population-based haematological malignancy research network 2004–2018. Eur. J. Haematol. 2021, 107, 211–218. [Google Scholar] [CrossRef] [PubMed]
- Jalbert, J.J.; Chaudhari, U.; Zhang, H.; Weyne, J.; Shammo, J.M. Epidemiology of PNH and real-world treatment patterns following an incident PNH diagnosis in the US. Blood 2019, 134, 3407. [Google Scholar] [CrossRef]
- Hansen, D.L.; Möller, S.; Andersen, K.; Gaist, D.; Frederiksen, H. Increasing incidence and prevalence of acquired hemolytic anemias in Denmark, 1980–2016. Clin. Epidemiol. 2020, 12, 497–508. [Google Scholar] [CrossRef]
- Bessler, M.; Mason, P.J.; Hillmen, P.; Miyata, T.; Yamada, N.; Takeda, J.; Luzzatto, L.; Kinoshita, T. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994, 13, 110–117. [Google Scholar] [CrossRef]
- Miyata, T.; Yamada, N.; Iida, Y.; Nishimura, J.; Takeda, J.; Kitani, T.; Kinoshita, T. Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 1994, 330, 249–255. [Google Scholar] [CrossRef]
- Takeda, J.; Miyata, T.; Kawagoe, K.; Iida, Y.; Endo, Y.; Fujita, T.; Takahashi, M.; Kitani, T.; Kinoshita, T. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993, 73, 703–711. [Google Scholar] [CrossRef]
- Yamashina, M.; Ueda, E.; Kinoshita, T.; Takami, T.; Ojima, A.; Ono, H.; Tanaka, H.; Kondo, N.; Orii, T.; Okada, N.; et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 1990, 323, 1184–1189. [Google Scholar] [CrossRef]
- Nicholson-Weller, A.; March, J.P.; Rosenfeld, S.I.; Austen, K.F. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc. Natl. Acad. Sci. USA 1983, 80, 5066–5070. [Google Scholar] [CrossRef]
- Hill, A.; DeZern, A.E.; Kinoshita, T.; Brodsky, R.A. Paroxysmal nocturnal haemoglobinuria. Nat. Rev. Dis. Primers 2017, 3, 17028. [Google Scholar] [CrossRef] [PubMed]
- Brodsky, R.A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009, 113, 6522–6527. [Google Scholar] [CrossRef] [PubMed]
- Nishimura, J.I.; Kanakura, Y.; Ware, R.E.; Shichishima, T.; Nakakuma, H.; Ninomiya, H.; Decastro, C.M.; Hall, S.; Kanamaru, A.; Sullivan, K.M.; et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine 2004, 83, 193–207. [Google Scholar] [CrossRef] [PubMed]
- Risitano, A.M.; Peffault de Latour, R. How we(‘ll) treat paroxysmal nocturnal haemoglobinuria: Diving into the future. Br. J. Haematol. 2022, 196, 288–303. [Google Scholar] [CrossRef] [PubMed]
- Panse, J. Paroxysmal nocturnal hemoglobinuria: Where we stand. Am. J. Hematol. 2023, 98, S20–S32. [Google Scholar] [CrossRef] [PubMed]
- Peffault de Latour, R.; Hosokawa, K.; Risitano, A.M. Hemolytic paroxysmal nocturnal hemoglobinuria: 20 years of medical progress. Semin. Hematol. 2022, 59, 38–46. [Google Scholar] [CrossRef]
- Hillmen, P.; Young, N.S.; Schubert, J.; Brodsky, R.A.; Socié, G.; Muus, P.; Röth, A.; Szer, J.; O Elebute, M.; Nakamura, R.; et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 2006, 355, 1233–1243. [Google Scholar] [CrossRef]
- Brodsky, R.A.; Young, N.S.; Antonioli, E.; Risitano, A.M.; Schrezenmeier, H.; Schubert, J.; Gaya, A.; Coyle, L.; de Castro, C.; Fu, C.-L.; et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008, 111, 1840–1847. [Google Scholar] [CrossRef]
- Hillmen, P.; Muus, P.; Dührsen, U.; Risitano, A.M.; Schubert, J.; Luzzatto, L.; Schrezenmeier, H.; Szer, J.; Brodsky, R.A.; Hill, A.; et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007, 110, 4123–4128. [Google Scholar] [CrossRef]
- Bektas, M.; Copley-Merriman, C.; Khan, S.; Sarda, S.P.; Shammo, J.M. Paroxysmal nocturnal hemoglobinuria: Current treatments and unmet needs. J. Manag. Care Spec. Pharm. 2020, 26 (Suppl. S12-b), S12–S20. [Google Scholar] [CrossRef]
- Sheridan, D.; Yu, Z.-X.; Zhang, Y.; Patel, R.; Sun, F.; Lasaro, M.A.; Bouchard, K.; Andrien, B.; Marozsan, A.; Wang, Y.; et al. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS ONE 2018, 13, e0195909. [Google Scholar] [CrossRef]
- Lee, J.W.; Sicre de Fontbrune, F.; Lee, W.; Lee, L.; Pessoa, V.; Gualandro, S.; Füreder, W.; Ptushkin, V.; Rottinghaus, S.T.; Volles, L.; et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: The 301 study. Blood 2019, 133, 530–539. [Google Scholar] [CrossRef] [PubMed]
- Kulasekararaj, A.G.; Hill, A.; Rottinghaus, S.T.; Langemeijer, S.; Wells, R.; Ataulfo Gonzalez-Fernandez, F.; Gaya, A.; Lee, J.W.; Ojeda Gutierrez, E.; Piatek, C.I.; et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: The 302 study. Blood 2019, 133, 540–549. [Google Scholar] [CrossRef]
- Kulasekararaj, A.G.; Griffin, M.; Langemeijer, S.; Usuki, K.; Kulagin, A.; Ogawa, M.; Yu, J.; Mujeebuddin, A.; Nishimura, J.-I.; Lee, J.W.; et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur. J. Haematol. 2022, 109, 205–214. [Google Scholar] [CrossRef] [PubMed]
- Yenerel, M.N.; Sicre de Fontbrune, F.; Piatek, C.; Sahin, F.; Füreder, W.; Ortiz, S.; Ogawa, M.; Ozol-Godfrey, A.; Sierra, J.R.; Szer, J. Phase 3 study of subcutaneous versus intravenous ravulizumab in eculizumab-experienced adult patients with PNH: Primary analysis and 1-year follow-up. Adv. Ther. 2023, 40, 211–232. [Google Scholar] [CrossRef] [PubMed]
- AstraZeneca. 9M and Q3 2023 Results. Available online: https://www.astrazeneca.com/investor-relations/9m-and-q3-2023-results.html (accessed on 1 October 2024).
- Terriou, L.; Piggin, M.; Burmester, P.; Zhang, F.; Finnegan, A.; Kritikou, P.; Mighiu, C.; Buehrer, C.; Katz, P.; Mode, S.; et al. P783: Clinical, humanistic, and economic burden in patients with PNH receiving C5 inhibition treatment across UK, Germany, and France. Insights from the COMMODORE Burden of Illness study. Hemasphere 2023, 7, e3528996. [Google Scholar] [CrossRef]
- Kaiser, K.; Yount, S.E.; Martens, C.E.; Webster, K.A.; Shaunfield, S.; Sparling, A.; Devin Peipert, J.; Cella, D.; Rottinghaus, S.T.; Donato, B.M.K.; et al. Assessing preferences for rare disease treatment: Qualitative development of the Paroxysmal Nocturnal Hemoglobinuria Patient Preference Questionnaire (PNH-PPQ). Patient Prefer. Adherence 2020, 14, 705–715. [Google Scholar] [CrossRef]
- Nishimura, J.; Yamamoto, M.; Hayashi, S.; Ohyashiki, K.; Ando, K.; Brodsky, A.L.; Noji, H.; Kitamura, K.; Eto, T.; Takahashi, T.; et al. Genetic variants in C5 and poor response to eculizumab. N. Engl. J. Med. 2014, 370, 632–639. [Google Scholar] [CrossRef]
- Igawa, T.; Ishii, S.; Tachibana, T.; Maeda, A.; Higuchi, Y.; Shimaoka, S.; Moriyama, C.; Watanabe, T.; Takubo, R.; Yoshiaki, D.; et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat. Biotechnol. 2010, 28, 1203–1207. [Google Scholar] [CrossRef]
- Sampei, Z.; Haraya, K.; Tachibana, T.; Fukuzawa, T.; Shida-Kawazoe, M.; Wan Gan, S.; Shimizu, Y.; Ruike, Y.; Feng, S.; Kuramochi, T.; et al. Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody. PLoS ONE 2018, 13, e0209509. [Google Scholar] [CrossRef]
- Nishimura, J.I.; Usuki, K.; Ramos, J.; Ichikawa, S.; Buri, M.; Kiialainen, A.; Sostelly, A.; Peffault de Latour, R.; Paz-Priel, I.; Röth, A. Crovalimab for treatment of patients with paroxysmal nocturnal haemoglobinuria and complement C5 polymorphism: Subanalysis of the phase 1/2 COMPOSER study. Br. J. Haematol. 2022, 198, e46–e50. [Google Scholar] [CrossRef] [PubMed]
- Fukuzawa, T.; Sampei, Z.; Haraya, K.; Ruike, Y.; Shida-Kawazoe, M.; Shimizu, Y.; Wan Gan, S.; Irie, M.; Tsuboi, Y.; Tai, H.; et al. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci. Rep. 2017, 7, 1080. [Google Scholar] [CrossRef] [PubMed]
- Strickley, R.G.; Lambert, W.J. A review of formulations of commercially available antibodies. J. Pharm. Sci. 2021, 110, 2590–2608.e56. [Google Scholar] [CrossRef] [PubMed]
- Tomar, D.S.; Kumar, S.; Singh, S.K.; Goswami, S.; Li, L. Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development. MAbs 2016, 8, 216–228. [Google Scholar] [CrossRef] [PubMed]
- Röth, A.; Nishimura, J.I.; Nagy, Z.; Gaàl-Weisinger, J.; Panse, J.; Yoon, S.S.; Egyed, M.; Ichikawa, S.; Ito, Y.; Kim, J.S.; et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 2020, 135, 912–920. [Google Scholar] [CrossRef]
- Röth, A.; Ichikawa, S.; Ito, Y.; Kim, J.S.; Nagy, Z.; Obara, N.; Panse, J.; Schrezenmeier, H.; Sica, S.; Soret, J.; et al. Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: Long-term results from the phase I/II COMPOSER trial. Eur. J. Haematol. 2023, 111, 300–310. [Google Scholar] [CrossRef]
- Scheinberg, P.; Clé, D.V.; Kim, J.S.; Nur, E.; Yenerel, M.N.; Barcellini, W.; Bonito, D.; Giai, V.; Hus, M.; Lee, Y.; et al. Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 2024, 99, 1757–1767. [Google Scholar] [CrossRef]
- Liu, H.; Xia, L.; Weng, J.; Zhang, F.; He, C.; Gao, S.; Jia, J.; Chang, A.C.; Lundberg, P.; Shi, J.; et al. Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor-naive patients with PNH (COMMODORE 3): A multicenter, Phase 3, single-arm study. Am. J. Hematol. 2023, 98, 1407–1414. [Google Scholar] [CrossRef]
- Röth, A.; He, G.; Tong, H.; Lin, Z.; Wang, X.; Chai-Adisaksopha, C.; Lee, J.H.; Brodsky, A.; Hantaweepant, C.; Dumagay, T.E.; et al. Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition. Am. J. Hematol. 2024, 99, 1768–1777. [Google Scholar] [CrossRef]
- Panse, J.; Cermak, J.; Kyselova, O.; Gotoh, A.; Sahin, F.; Schrezenmeier, H.; Chang, A.C.; Gentile, B.; Uguen, M.; Han, B. Patient-reported outcomes (PROs) in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with crovalimab and eculizumab: Results from the phase III randomized COMMODORE 2 and COMMODORE 1 trials. Blood 2023, 142 (Suppl. 1), 4090. [Google Scholar] [CrossRef]
- PiaSky (Crovalimab) [Prescribing Information]; Genentech, Inc.: South San Francisco, CA, USA, 2024.
- Chugai Pharmaceutical Co., Ltd. Chugai Obtains Regulatory Approval for “PiaSky 340 mg” for Paroxysmal Nocturnal Hemoglobinuria in Japan. Available online: https://www.chugai-pharm.co.jp/english/news/detail/20240326160001_1056.html (accessed on 1 April 2024).
- PiaSky (Crovalimab) [Summary of Product Characteristics]; Roche Registration GmbH: Grenzach-Wyhlen, Germany, 2024.
- Chugai Pharmaceutical Co., Ltd. Crovalimab Approved in China as the First Country, for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). Available online: https://www.chugai-pharm.co.jp/english/news/detail/20240208113000_1047.html?year=2024&category= (accessed on 27 February 2024).
- Maeda, A.; Iwayanagi, Y.; Haraya, K.; Tachibana, T.; Nakamura, G.; Nambu, T.; Esaki, K.; Hattori, K.; Igawa, T. Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody. MAbs 2017, 9, 844–853. [Google Scholar] [CrossRef] [PubMed]
- Maadi, H.; Soheilifar, M.H.; Choi, W.S.; Moshtaghian, A.; Wang, Z. Trastuzumab mechanism of action; 20 years of research to unravel a dilemma. Cancers 2021, 13, 3540. [Google Scholar] [CrossRef] [PubMed]
- Sissons, J.G.; Liebowitch, J.; Amos, N.; Peters, D.K. Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation. J. Clin. Investig. 1977, 59, 704–715. [Google Scholar] [CrossRef] [PubMed]
- Yang, M.X.; Shenoy, B.; Disttler, M.; Patel, R.; McGrath, M.; Pechenov, S.; Margolin, A.L. Crystalline monoclonal antibodies for subcutaneous delivery. Proc. Natl. Acad. Sci. USA 2003, 100, 6934–6939. [Google Scholar] [CrossRef]
- Sostelly, A.; Buatois, S.; Soubret, A.; Winter, E.; Klughammer, B.; Hsu, J.C.; Jordan, G.; Bucher, C.; Charoin, J.E.; Gotanda, K.; et al. Exposure-response relationship of the SMART-Ig anti-hC5 antibody crovalimab (SKY59): Results from the umbrella phase 1/2 composer trial in healthy volunteers and PNH patients. Blood 2019, 134, 3745. [Google Scholar] [CrossRef]
- Vidarsson, G.; Dekkers, G.; Rispens, T. IgG subclasses and allotypes: From structure to effector functions. Front. Immunol. 2014, 5, 520. [Google Scholar] [CrossRef]
- Rother, R.P.; Rollins, S.A.; Mojcik, C.F.; Brodsky, R.A.; Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 2007, 25, 1256–1264. [Google Scholar] [CrossRef]
- Peffault de Latour, R.; Brodsky, R.A.; Ortiz, S.; Risitano, A.M.; Jang, J.H.; Hillmen, P.; Kulagin, A.D.; Kulasekararaj, A.G.; Rottinghaus, S.T.; Aguzzi, R.; et al. Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: Results of two phase 3 randomised, multicentre studies. Br. J. Haematol. 2020, 191, 476–485. [Google Scholar] [CrossRef]
- Tadaka, S.; Katsuoka, F.; Ueki, M.; Kojima, K.; Makino, S.; Saito, S.; Otsuki, A.; Gocho, C.; Sakurai-Yageta, M.; Danjoh, I.; et al. 3.5KJPNv2: An allele frequency panel of 3552 Japanese individuals including the X chromosome. Hum. Genome Var. 2019, 6, 28. [Google Scholar] [CrossRef]
- Langemeijer, S.; Nishimura, J.I.; Weston-Davies, W.; Nunn, M.A.; Kanakura, Y.; Mackie, I.J.; Muus, P. C5 polymorphism in a Dutch patient with paroxysmal nocturnal hemoglobinuria (PNH) and no Asian ancestry, resistant to eculizumab, but in vitro sensitive to coversin. Blood 2015, 126, 1209. [Google Scholar] [CrossRef]
- Sampei, Z.; Koo, C.X.E.; Teo, F.J.; Toh, Y.X.; Fukuzawa, T.; Wan Gan, S.; Nambu, T.; Ho, A.; Honda, K.; Igawa, T.; et al. Complement activation by an anti-dengue/zika antibody with impaired Fcγ receptor binding provides strong efficacy and abrogates risk of antibody-dependent enhancement. Antibodies 2023, 12, 36. [Google Scholar] [CrossRef] [PubMed]
- Haraya, K.; Tachibana, T.; Iwayanagi, Y.; Maeda, A.; Ozeki, K.; Nezu, J.; Ishigai, M.; Igawa, T. PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody-antigen binding model. Drug. Metab. Pharmacokinet. 2016, 31, 123–132. [Google Scholar] [CrossRef] [PubMed]
- Haraya, K.; Tachibana, T. Simple approach to accurately predict pharmacokinetics of therapeutic monoclonal antibodies after subcutaneous injection in humans. Clin. Pharmacokinet. 2021, 60, 111–120. [Google Scholar] [CrossRef] [PubMed]
Antibody | pH 7.4 | pH 5.8 | Ratio of KD at pH 5.8/pH 7.4 | ||||
---|---|---|---|---|---|---|---|
ka (1/Ms) | kd (1/s) | KD (M) | ka (1/Ms) | kd (1/s) | KD (M) | ||
Crovalimab | 7.41 × 105 | 1.23 × 10−4 | 1.66 × 10−10 | 1.25 × 105 | 1.64 × 10−2 | 1.32 × 10−7 | 796 |
Ravulizumab-SIA | 6.07 × 105 | 8.39 × 10−4 | 1.38 × 10−9 | 2.64 × 105 | 3.38 × 10−2 | 1.28 × 10−7 | 92.4 |
Eculizumab-SIA | 1.33 × 106 | 1.89 × 10−4 | 1.42 × 10−10 | 1.45 × 106 | 3.82 × 10−3 | 2.64 × 10−9 | 18.6 |
Human C5 | |||
---|---|---|---|
C5 concentration [36] | 134 μg/mL (704 nM) | ||
C5 clearance [48] | 17.0 mL/day/kg | ||
C5 production per day | 12.0 nmol/day/kg (897 nmol/day for 75 kg body weight) | ||
Eculizumab | Ravulizumab | Crovalimab | |
Maintenance dosing regimen [22,23,38,40] | 900 mg IV Q2W | 3300 mg IV Q8W | 680 mg SC (501 mg bioavailable *) Q4W |
Antibody dose per day | 64.3 mg/day (434 nmol/day) | 58.9 mg/day (398 nmol/day) | 17.9 mg/day (121 nmol/day) |
Ratio of C5 production per day to antibody dose per day | 897/434 = 2.07 2.07 C5 molecules per antibody | 897/398 = 2.25 2.25 C5 molecules per antibody | 897/121 = 7.42 7.42 C5 molecules per antibody |
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Sampei, Z.; Haraya, K.; Gan, S.W.; Muraoka, M.; Hayasaka, A.; Fukuzawa, T.; Shida-Kawazoe, M.; Tsuboi, Y.; Gotoh, A.; Obara, N.; et al. Beyond Recycling Antibodies: Crovalimab’s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment. Int. J. Mol. Sci. 2024, 25, 11679. https://doi.org/10.3390/ijms252111679
Sampei Z, Haraya K, Gan SW, Muraoka M, Hayasaka A, Fukuzawa T, Shida-Kawazoe M, Tsuboi Y, Gotoh A, Obara N, et al. Beyond Recycling Antibodies: Crovalimab’s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment. International Journal of Molecular Sciences. 2024; 25(21):11679. https://doi.org/10.3390/ijms252111679
Chicago/Turabian StyleSampei, Zenjiro, Kenta Haraya, Siok Wan Gan, Masaru Muraoka, Akira Hayasaka, Taku Fukuzawa, Meiri Shida-Kawazoe, Yoshinori Tsuboi, Akihiko Gotoh, Naoshi Obara, and et al. 2024. "Beyond Recycling Antibodies: Crovalimab’s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment" International Journal of Molecular Sciences 25, no. 21: 11679. https://doi.org/10.3390/ijms252111679
APA StyleSampei, Z., Haraya, K., Gan, S. W., Muraoka, M., Hayasaka, A., Fukuzawa, T., Shida-Kawazoe, M., Tsuboi, Y., Gotoh, A., Obara, N., & Ueda, Y. (2024). Beyond Recycling Antibodies: Crovalimab’s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment. International Journal of Molecular Sciences, 25(21), 11679. https://doi.org/10.3390/ijms252111679