Tilvestamab: A Comprehensive Overview

1. Background Study

In recent times, many cancerous diseases form of uncontrolled cell division, especially non-small cell lung cancer (NSCLC), melanoma, and breast cancer. Based on statistics from the American Cancer Society, NSCLC accounts for 80% to 85% of all lung cancers [1]. Meanwhile, it is reported that the rate of affected Melanoma skin cancer is 21 per lakh per year, but it causes a significant number of deaths [2]. Moreover, breast cancer is most common in women and causes 670,000 deaths globally in 2022, followed by WHO [3]. Despite conventional cancer treatments, monoclonal antibody therapies like Tilvestamab are effectively able to kill cancer cells, block their growth, and spread [4]. 

2. Target and its mechanism

Tilvestamab or BGB149 is a novel humanized monoclonal antibody directed towards the AXL receptor tyrosine kinase, a relative of the TAM family of receptor tyrosine kinases, which regulates cell survival, growth and migration [5, 6]. In addition, the overexpression of AXL has been extensively linked with numerous cancers and has a role in supporting tumorigenesis, metastasis, and resistance to therapy. So, inhibition of AXL would be a window for drug development. Here, Tilvestamab binds with AXL, preventing the advancement of cancers [4, 7].   

3. Medicinal usage

Tislelizumab, developed by BerGenBio, is currently tested as a potential therapy for a range of solid tumors, including NSCLC, melanoma, and breast cancer [5]. As noted by Chen et al., Tislelizumab is currently evaluated as a monotherapy and in combination with other anti-cancer drugs, such as Sunitinib or Bemcentinib [6]. 

4. Clinical study results

Recent clinical trials have reported promising outcomes regarding the use of Tilvestamab in solid tumors. In 2022, a phase I clinical trial revealed that Tilvestamab was well-tolerated and exhibited remarkable anticancer properties in individuals with solid tumors [8, 9]. A phase II study initiated in 2023 assesses the antitumor efficacy and safety of Tilvestamab in combination with Pembrolizumab in patients with advanced NSCLC [9]. 

5. Side effects

Although clinical trials have shown a very good safety profile for Tilvestamab, some common issues have been observed, including infusion-related reactions, fatigue, and gastrointestinal symptoms. Serious adverse events are rarely reported and are all manageable [10].

6. Molecular engineering and development

Tilvestamab was developed using humanization techniques and is produced in Chinese hamster ovary (CHO) cells [5]. The antibody was engineered to have high affinity and specificity for AXL while minimizing potential immunogenicity [11]. 

7. Potential drug interactions

Considering that Tilvestamab is administered with other anti-cancer agents, patients should be warned about potential drug interactions. Although the combination of Tilvestamab and immune checkpoint inhibitors may have a beneficial effect on the immune response, it can increase the incidence and severity of immune-related adverse events [7, 12]. 

8. New prospective uses

Tilvestamab is not limited to its effectiveness in solid tumors but is being translated into other categories of cancer, such as acute myeloid leukemia (AML) and glioblastoma [13, 8]. Tilvestamab is also under investigation in combination with an innovative therapeutic strategy such as chimeric antigen receptor (CAR) T-cell therapy [14].

9. Other antibodies in clinical development

Currently, several other AXL-targeted monoclonal antibodies such as enapotamab vedotin and CAB-AXL-ADC (AXL-Targeted antibody-drug conjugate) being examined in clinical trials in cancer therapy [15, 16].  

Ichorbio is a high-quality manufacturer of biosimilars and has developed a Tilvestamab biosimilar. Find the product: https://ichor.bio/tilvestamab-biosimilar-research-grade

References: 

1. https://www.cancer.org/cancer/types/lung-cancer/about/what-is.html  [Extracted Information on 13 April 2024]

2. https://seer.cancer.gov/statfacts/html/melan.html  [Extracted Information on 13 April 2024]

3. https://www.who.int/news-room/fact-sheets/detail/breast-cancer [Extracted Information on 13 April 2024] 

4. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq [Extracted Information on 13 April 2024]

5. https://www.bergenbio.com/pipeline/bgb149  [Extracted Information on 13 April 2024]

6. Chen TJ, Mydel P, Benedyk-Machaczka M, Kamińska M, Kalucka U, et al. AXL targeting by a specific small molecule or monoclonal antibody inhibits renal cell carcinoma progression in an orthotopic mice model. Physiol Rep. 2021 Dec;9(23): e15140. 

7. Zhai X, Pu D, Wang R, et al. Gas6/AXL pathway: immunological landscape and therapeutic potential. Frontiers in Oncology. 2023; 13:1121130. 

8. Mikolajczyk A, Mitula F, Popiel D, Kaminska B, Wieczorek M, Pieczykolan J. Two-Front War on Cancer-Targeting TAM Receptors in Solid Tumour Therapy. Cancers (Basel). 2022 May 18;14(10):2488. 

9. https://classic.clinicaltrials.gov/ct2/show/NCT04893551 [Extracted Information on 15 April 2024]

10. Bio M, Hodneland Nilsson L, Jackson A, et al. Tilvestamab, a novel clinical stage humanized anti-AXL function blocking antibody. European Journal of Cancer, 2020: 138(2).

11. https://www.medchemexpress.com/tilvestamab.html [[Extracted Information on 15 April 2024]

12. Yin, H., Hua, Y., Feng, S., Xu, Y., Ding, Y., Liu, S., Chen, D., Du, F., Liang, G., Zhan, W., & Shen, Y. In Situ Nanofiber Formation Blocks AXL and GAS6 Binding to Suppress Ovarian Cancer Development. Advanced Materials, 2308504.

13. Niu X, Rothe K, Chen M, Grasedieck S, Li R, Nam SE, et al. Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia. Blood. 2021 Jul 1;137(26):3641-3655.

14. Abbasi S, Totmaj MA, Abbasi M, Hajazimian S, et al. Chimeric antigen receptor T (CAR-T) cells: Novel cell therapy for hematological malignancies. Cancer Med. 2023 Apr;12(7):7844-7858. 

15. Van Renterghem B, Wozniak A, Castro PG, Franken P, Pencheva N, Sciot R, Schöffski P. Enapotamab Vedotin, an AXL-Specific Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma. Int J Mol Sci. 2022 Jul 6;23(14):7493. 

16. Koopman LA, Terp MG, Zom GG, Janmaat ML, Jacobsen K, et al. Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer. JCI Insight. 2019 Nov 1;4(21): e128199.