Alsevalimab: A Comprehensive Overview

1.  Background study

Solid tumors are abnormal cell division without any cysts or liquid, such as sarcomas and carcinomas [1]. According to the American Cancer Society (ACS), around 90% of adult and 40 % of children cancers are associated with solid tumors [2]. Several effective medications exist, including antibody therapies in solid tumors [3]. However, Alsevalimab as a glycoengineered antibody makes a significant hope against negative regulation of T-cell activation in the tumors [4]. 

2.  Target and its mechanism

Alsevalimab, a complete human monoclonal antibody, targets particularly B7-B4 protein (V-set domain-containing T-cell activation inhibitor 1; VTCN1; B7x; B7S1), which is a member of the B7 family protein of immune checkpoints. In medical science, the overexpression of B7-H4 protein stimulates poor prognosis and immune evasion in various solid tumors. Alsevalimab is administered intravenously and binds to B7-H4 to block its interaction with T cells, promoting tumor cell death and enhancing the antitumor immune response [4, 5]. 

3. Medicinal usage

Recent studies investigate Alsevalimab as a potential drug and find positive outcomes in different cancerous diseases, including breast, ovarian, endometrial, and non-small cell lung cancer (NSCLC). It is not only used as a monotherapy but is also combined with anti-PD-1/PD-L-1 ((Programmed Cell Death-1/ Programmed Cell Death Ligand-1), which is another type of immune checkpoint [6, 7]. 

4. Clinical study results

Alsevalimab has had significant results during the current clinical study in the aspect of tumor treatment. Sachdev JC et al. demonstrated that the tolerance rate of FPA150 (Alsevalimab) in the phase I trial was satisfactory in the severe stage of solid tumor patients, specifically ovarian cancer, in 2019. Another study reported in 2023 that it combined with Pembrolizumab showed better response and survival rates than Pembrolizumab alone in severe NSCLC patients [9, 10, 8].  

5. Site effects

Alsevalimab illustrated controllable side effects during clinical trials. Additionally, some typical safety issues, like fatigue, nausea, and reduced appetite, are found. However, a few adverse problems, including hypothyroidism and pneumonitis, have rarely been observed, but all are manageable if there is a proper monitoring system [11, 5]. 

6. Molecular engineering and development

Alsevalimab was developed using a bioengineering technique produced in Chinese hamster ovary (CHO) cells. The antibody was designed to mitigate possible immunogenicity while having a high affinity and specificity for the B7-H4 protein [10]. The binding of Alsevalimab to B7-H4 prevents the interaction with its receptor on T cells, thereby enhancing the antitumor immune response [4, 12].

7. Potential drug interactions

As an immune checkpoint agent, it should have prospective drug interactions with similar types of immunomodulatory inhibitors [6]. For example, combining Alsevalimab and anti-PD-1/PD-L1 antibodies may boost the immune system’s effectiveness despite unlikely immunological side effects. In addition, it interacts with various chemotherapeutic agents and targeted therapies to ensure their efficacy and safety [11, 13].

8. New prospective uses

Alsevalimab is being investigated as a possible treatment for hematologic malignancies and brain tumors, in addition to its well-established involvement in solid tumors [14]. Moreover, to potentially induce its therapeutic efficacy, Alsevalimab is being studied in conjunction with cutting-edge uses in cancer vaccines and chimeric antigen receptor (CAR) T-cell therapy [15].

9. Other antibodies in clinical development

Several additional B7-H4-targeted monoclonal antibodies are currently developed clinically to treat cancer, including MGA012, a humanized anti-B7-H4 antibody, and FPA150, a B7-H4-targeted antibody-drug combination [16, 17]. Furthermore, as prospective therapeutic alternatives, bispecific antibodies that target B7-H4 and other immune checkpoint proteins like PD-1 or CTLA-4 (Cytotoxic T-lymphocyte Associated Antigen 4) are being researched [18].

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References: 

1. https://www.stjude.org/treatment/disease/solid-tumors/what-is-solid-tumor.html#:~:text=Two%20major%20types%20of%20solid,are%20many%20types%20of%20sarcomas. [Extracted Information on 25 April 2024] 

2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17-48. 

3. Guha P, Heatherton KR, O'Connell KP, Alexander IS, Katz SC. Assessing the Future of Solid Tumor Immunotherapy. Biomedicines. 2022 Mar 11;10(3):655. 

4. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alsevalimab?redirect=true [Extracted Information on 25 April 2024] 

5. Hassanian H, Asadzadeh Z, Baghbanzadeh A, Derakhshani A, Dufour A, Rostami Khosroshahi N, Najafi S, Brunetti O, Silvestris N, Baradaran B. The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment. Front Immunol. 2022 Jul 28; 13:938063. 6. Vaishnav J, Khan F, Yadav M, Parmar N, Buch H, Jadeja SD, Dwivedi M, Begum R. V-set domain containing T-cell activation inhibitor-1 (VTCN1): A potential target for the treatment of autoimmune diseases. Immunobiology. 2022 Nov;227(6):152274. 

7. Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, Ladwa R, O'Byrne K, Kulasinghe A. Immune Checkpoint Inhibitors in Cancer Therapy. Curr Oncol. 2022 Apr 24;29(5):3044-3060.

8. Ludford K, Ho WJ, Thomas JV, Raghav KPS, Murphy MB, Fleming ND, Lee MS, Smaglo BG, You YN, Tillman MM, Kamiya-Matsuoka C, Thirumurthi S, Messick C, Johnson B, Vilar E, Dasari A, Shin S, Hernandez A, Yuan X, Yang H, Foo WC, Qiao W, Maru D, Kopetz S, Overman MJ. Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors. J Clin Oncol. 2023 Apr 20;41(12):2181-2190. 

9. https://clinicaltrials.gov/study/NCT03514121 [Extracted Information on 25 April 2024]

10. Jasgit C. Sachdev et al. Phase 1a/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors.. JCO 37, 2529-2529(2019).

11. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018 Mar 14;360: k793. 

12. Wang JY, Wang WP. B7-H4, a promising target for immunotherapy. Cell Immunol. 2020 Jan; 347:104008. doi: 10.1016/j.cellimm.2019.104008. Epub 2019 Nov 4. 

13. Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022 Jan 21;21(1):28. 

14. Yuan Z, Gardiner JC, Maggi EC, Huang S, Adem A, Bagdasarov S, Li G, Lee S, Slegowski D, Exarchakis A, Howe JR, Lattime EC, Zang X, Libutti SK. B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors. Endocr Relat Cancer. 2021 Feb;28(2):135-149. 

15. Ansah EO et al. Vaccine Boosting CAR-T Cell Therapy: Current and Future Stratigies. Advances in Cell and Gene Therapy, 2023.   

16.  C.D. Kaplan, D. Houser, F. Kemp et al. FPA150, a novel B7-H4 therapeutic antibody with checkpoint blockade and ADCC activities. Annals of Oncology, 2017; 28(2):8-12.

17. Feustel K, Martin J, Falchook GS. B7-H3 Inhibitors in Oncology Clinical Trials: A Review. J Immunother Precis Oncol. 2024 Feb 5;7(1):53-66. 

18. Yu L, Sun M, Zhang Q, Zhou Q, Wang Y. Harnessing the immune system by targeting immune checkpoints: Providing new hope for Oncotherapy. Front Immunol. 2022 Sep 8; 13:982026.