Enfortumab vedotin-ejfv (Padcev™; Astellas Pharma / Seattle Genetics) is a Nectin-4-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.
Approval
This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Conjugate
The Nectin-4 directed antibody-drug conjugate (ADC) is comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3), produced by mammalian (Chinese hamster ovary/CHO) cells, conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC; SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio (DAR) of approximately 3.8:1.
The molecular weight is approximately 152 kDa.
First-in-class
Enfortumab vedotin, also known as ASG-22ME, is a first-in-class antibody-drug conjugate or ADC that is directed against Nectin-4 (Poliovirus Receptor-related 4; PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, located on the surface of cells and highly expressed in bladder cancer.
After internalization and proteolytic cleavage, MMAE binds to tubulin and inhibits its polymerization, which results in G2/M phase arrest and induces apoptosis in Nectin-4 overexpressing tumor cells. Nectin-4, a tumor associated antigen belonging to the nectin family, is overexpressed in a variety of cancers.
Analysis of protein expression carried out in an extensive panel of tumor specimens by immunohistochemistry confirmed strong to moderate expression levels of Nectin-4 in bladder, breast and pancreatic cancers (40-60%). A subset of lung and ovarian cancers (up to 30%) also showed significant expression levels of this protein.
Mechanism of Action
Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to cells expressing Nectin-4. After internalization and proteolytic cleavage, the anti-tumor payload MMAE binds to tubulin and inhibits its polymerization, which results in G2/M phase arrest and induces apoptosis (programmed cell death) in Nectin-4 overexpressing tumor cells. [1][2]
Structural formula enfortumab vedotin.Development
In the early development of enfortumab vedotin, scientists at Agensys (Santa Monica, CA, 90404)* prepared hybridoma (AGS-22M6E) and CHO (ASG-22CE)** versions of enfortumab vedotin (also known as ASG-22ME), targeting Nectin-4 (Agensys code name AGS-22).
They were able to bind the the versions of enfortumab vedotin to cell surface expressed Nectin-4, a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules and reported high affinity and induced cell death in vitro in a dose-dependent manner.
In this early phase, using mouse xenograft models of human breast, bladder, pancreatic, and lung cancers, scientists found that treatment with enfortumab vedotin significantly inhibited the growth these tumor types. They also noted tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.
Clinical trials
Enfortumab vedotin is currently in be investigated in a number of clinical trials.
- A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (EV-201) – NCT03219333
- A Study of Enfortumab Vedotin in Japanese Subjects With Locally Advanced or Metastatic Urothelial Carcinoma – NCT03070990
- A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
- An Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma – NCT04136808
- A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
- A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4 – NCT02091999
- A Study of the Safety and Pharmacokinetics of AGS-22M6E in Subjects With Malignant Solid Tumors That Express Nectin-4 – NCT01409135
- A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-based Treatment Combinations in Patients With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy (MORPHEUS mUC) – NCT03869190
Availability
Enfortumab vedotin-ejfv is available in 20 mg and 30 mg and is supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials of
- one 20 mg single-dose vial (NDC 51144-020-01) and
- one 30 mg single-dose vial (NDC 51144-030-01)
Note
* Now Astellas Pharma
** AGS-22M6E and ASG-22CE are fully human monoclonal antibody conjugated to a cytotoxic agent monomethyl auristatin E (MMAE) The main difference between AGS-22M6E and ASG-22CE is the change in cell line for antibody production
Reference
[1] Highlights of Prescription Information Padcev™. Astellas, Inc. [Package Insert]
[2] Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016;76(10):3003–3013. doi:10.1158/0008-5472.CAN-15-1313 [Pubmed][Article]
