Naptumomab Estafenatox

Naptumomab Estafenatox, “naptumomab” is a tumor targeting immunotherapy that enhances the ability of the immune system to recognize and kill the tumor. Since October 2016, Active Biotech has a licensing agreement with NeoTX Therapeutics Ltd. for the worldwide development and commercialization of naptumomab for cancer therapy.

Mode of Action and Therapy Concept

Naptumomab, a Tumor Targeting Superantigen (TTS), is a fusion protein containing the Fab-fragment of an antibody that targets the tumor-associated 5T4 antigen. 5T4 is expressed in a high number of solid tumors. The antibody part is fused with an engineered bacterial superantigen that activates T cells expressing a particular set of T cell receptors.

Naptumomab activates T lymphocytes and targets them to the 5T4-expressing tumors, resulting in massive effector lymphocyte infiltration into the tumor and tumor cell killing.

Mode of Action for NAPTUMOMAB

Naptumomab increases tumor recognition and redirect specific T cells to trigger tumor killing

So-called “programmed death 1/ligand 1” (PD-1/L1) antibodies are a new group of cancer drugs, checkpoint inhibitors, which function by unleashing the immune system to attack the tumor. Despite the successes of recent years with these immunotherapies, it remains a challenge for the immune system to recognize tumor cells and there is a need to optimize the therapeutic effect of checkpoint inhibitors. Naptumomab increases the immune system’s ability to recognize and attack the tumor and preclinical data from several different experimental models show synergistic anti-tumor effects and prolonged overall survival when naptumomab is combined with checkpoint inhibitors.

Clinical Trials

The safety and tolerability of naptumomab as mono therapy and in combination with standard cancer therapy, has been established in clinical trials encompassing more than 300 patients. The previous clinical development of naptumomab includes phase 1 studies in patients with advanced non-small cell lung cancer, renal cell carcinoma and pancreatic cancer and a phase 2/3 trial in combination with interferon alpha in patients with renal cell carcinoma.

Naptumomab enhances tumor recognition

Phase 1b/2 in advanced solid tumors

Ongoing

An open-label, multicenter, dose-finding clinical phase 1b/2 study with naptumomab in combination with durvalumab, a PD-1/L1 checkpoint inhibitor, is ongoing. The clinical trial will enroll patients with previously treated advanced or metastatic, 5T4-positive solid tumors and aims to establish the maximum tolerated dose in the phase 1b study before advancing to a phase 2 cohort expansion study. The trial was initiated in the second half of 2019 and is performed under an agreement with AstraZeneca. More information about the study is available at clinicaltrials.gov (NCT03983954) and atneotx.com.

Phase 1 in solid tumors

Completed

In the clinical phase 1 trials, naptumomab was studied both as a single agent and in combination with an established tumor therapy – docetaxel (Taxotere®) – in patients with advanced lung cancer, renal cell cancer or pancreatic cancer (Borghaei et al, 2009; ClinicalTrials: NCT00056537 and NCT00132379). The results showed that naptumomab was well tolerated both as monotherapy and in combination with docetaxel. The phase 1 results also showed proof-of-concept in terms of increased immunologic activity, including systemic increase of inflammatory cytokines, expansion of naptumomab reactive T cells and induction of infiltrating T cells.

Phase 2/3 in renal cell cancer

Completed

Results from the naptumomab phase 2/3 clinical study in patients with advanced renal cell cancer were announced in January 2013 (Hawkins et al, 2016; Elkord et al, 2015). The study encompassed 513 patients and was designed to evaluate the effect of naptumomab in combination with interferon-alpha, compared with interferon-alpha alone. The phase 2/3 study did not achieve its primary endpoint showing a prolonged overall survival in the patient population. The safety profile was good and in line with previous observations.

Publications

Selective T cell Redirection Proteins (STR) Enhance the Anti-Tumor Activity of Checkpoint Inhibitors (CPIs) and can Lead to Long-Lasting Immunity Againstthe Tumor. Meir Azulay, Sveta Lifshits, EitanShany, Adam Friedmann, Gunnar Hedlund and Michal Shahar. NeoTXTherapeuticsLTD, Rehovot, Israel. View the complete poster here.

Naptumomab Estafenatox induces T cell recognition, turning anti-PD-1 unresponsive “cold” tumors into “hot” responsive tumors. Azulay M, Lifshits S, Fridman A, Hedlund G, Törngren M, Shahar M. Poster presentation at AACR Annual Meeting 2018. View the complete poster here.

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis. Hawkins R, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. Clin Cancer Res. 2016; 22(13): 3172-81

Immunological response and overall survival in a subset of advanced renal cell carcinoma patients from a randomized phase 2/3 study of naptumomab estafenatox plus IFN-α versus IFN-α. Elkord E, Burt DJ, Sundstedt A, Nordle Ö, Hedlund G, Hawkins R. Oncotarget. 2015; 6(6): 4428-39

Naptumomab Estafenatox: targeted Immunotherapy with a Novel Immunotoxin. Eisen T, Hedlund G, Forsberg G, Hawkins R. Curr Oncol Rep. 2014; 16: 370

The tumor targeted superantigen ABR-217620 selectively engages TRBV7-9 and exploits TCR-pMHC affinity mimicry in mediating T cell cytotoxicity. Hedlund G, Eriksson H, Sundstedt A, Forsberg G, Jakobsen BK, Pumphrey N, Rödström K, Lindkvist-Petersson K, Björk P. PLoS One. 2013; 8(10): e79082

Monotherapeutically Nonactive CTLA-4 Blockade Results in Greatly Enhanced Antitumor Effects When Combined With Tumor-targeted Superantigens in a B16 Melanoma Model. Sundstedt A, Celander M, Eriksson H, Törngren M, Hedlund G. J Immunother. 2012; 35(4): 344–53

Tumor-Targeted Superantigens, in Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges. Hedlund G, Forsberg G, Nederman T, Sundstedt A, Dahlberg L, Tiensuu M, Nilsson, M. (ed S. R. Schmidt) 2013; p365-381, John Wiley & Sons, Inc., Hoboken, NJ, USA

Naptumomab estafenatox: a new immunoconjugate. Robinson MK, Alpaugh KR, Borghaei H. Expert Opin Biol Ther. 2010; 10: 273-79

Naptumomab estafenatox, an engineered antibody-superantigen fusion protein with low toxicity and reduced antigenicity. Forsberg G, Skartved N-J, Wallén-Öhman M, Carlsson-Nyhlen H, Behm K, Hedlund G, Nederman T. J Immunother. 2010; 33: 492-9

Phase I dose escalation, pharmakokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non small-cell lung cancer. Borghaei H, Alpaugh K, Hedlund G, Forsberg G, Langer C, Rogatko A, Hawkins R, Dueland S, Lassen U, Cohen RB. J Clin Oncol. 2009; 27: 4116-23