Naptumomab

Naptumomab estafenatox (naptumomab) is a tumor targeting immunotherapy that enhances the ability of the immune system to recognize and kill the tumor. Naptumomab is developed for treatment of solid tumors by Active Biotech’s partner NeoTX.

This is naptumomab

Naptumomab, a Tumor Targeting Superantigen (TTS), is a fusion protein containing the Fab-fragment of an antibody that targets the tumor-associated 5T4 antigen which is expressed in a high number of solid tumors. The antibody part of naptumomab is fused with an engineered bacterial superantigen that activates specific T cells expressing a particular set of T cell receptors. In short, naptumomab functions by activating T cells and re-direct them to 5T4-expressing tumors. This leads to a massive infiltration of effector T cells into the tumor and tumor cell killing.

Mode of Action for NAPTUMOMAB

Solid tumors

Cancer is a collective name for a large group of diseases characterized by the growth of abnormal cells, which can invade adjacent parts of the body or spread to other organs. Cancer is the second most common cause of death in the world. Lung, prostate, rectal, stomach and liver cancer are the most common types of cancer among men, while breast, rectal, lung, cervical and thyroid cancer are the most common types among women (www.who.int/health-topics/cancer).

The market

Immunotherapy is one of the major breakthroughs of recent years in cancer therapy, which is reflected in the checkpoint inhibitors Keytruda, Opdivo, Imfinzi and Tecentriq achieving combined global sales of USD 30.7 billion in 2021 (Global Data report 2022). The strong sales development for checkpoint inhibitors is expected to continue and sales are forecasted at USD 60.0 billion in 2028 (Global Data report 2022).

Current treatments

Treatment of solid tumors generally combines several types of therapy, which traditionally may include surgery, chemotherapy, and radiation therapy. Immunotherapy has been of decisive importance for cancer care in recent years, and the immunooncology market has demonstrated strong growth. Therapies aimed at targeting immune suppression are dominated by biological drugs classified as checkpoint inhibitors. Several new checkpoint inhibitors have been approved for various types of solid tumors.

Naptumomab in solid tumors

Naptumomab increases the immune system’s ability to recognize and attack the tumor and preclinical data from various experimental models show synergistic anti-tumor effects and prolonged overall survival when naptumomab is combined with checkpoint inhibitors.

Checkpoint inhibitors are a group of cancer drugs which function by unleashing the immune system to attack the tumor. Despite the successes in recent years with these immunotherapies in the treatment of solid tumors, 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.

Ongoing clinical development

Two studies are currently in progress:

  • An open-label, multicenter, dose-finding clinical phase Ib/II study is ongoing with naptumomab in combination with the checkpoint inhibitor durvalumab.
  • An open label clinical phase IIa study in US testing naptumomab in combination with docetaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) previously treated with checkpoint inhibitors.

More information about the ongoing studies can be found in the boxes below.

Previous clinical experience with naptumomab

Safety and tolerability of naptumomab as monotherapy and in combination with standard treatment have been established in clinical studies that include more than 300 patients.

Clinical development of naptumomab includes phase I studies in patients suffering from advanced non-small cell lung cancer, renal cell cancer and pancreatic cancer and a phase II/III study in combination with interferon alpha in patients with renal cell cancer.

Combining checkpoint inhibitors with the unique mode of action of naptumomab could be a useful strategy to treat multiple types of cancers, not responding to checkpoint inhibitors alone.

Naptumomab enhances tumor recognition

Phase Ib/II in advanced solid tumors

Ongoing

An open-label, multicenter, dose-finding clinical phase Ib/II study is ongoing with naptumomab in combination with the checkpoint inhibitor durvalumab. The clinical trial enrolls patients with previously treated advanced or metastatic, 5T4-positive solid tumors. The phase Ib part of the study is completed and the recommended phase II dose (RP2D) established. The trial was initiated in H2 2019 and is performed under an agreement with AstraZeneca. Interim safety and preliminary efficacy data from the study were presented at the American Association for Cancer Research (AACR) annual meeting in Orlando, Florida in April 2023. Data based on 59 patients with previously treated advanced or metastatic disease demonstrate that naptumomab in combination with durvalumab is well tolerated with limited toxicity at the RP2D. Durable, including complete, treatment responses were seen in patients where response to checkpoint inhibitor alone was not expected. In addition, the results indicate that pretreatment with obinutuzumab, a B-cell therapy, reduces the formation of anti-drug antibodies against naptumomab. A cohort expansion of this trial with patients suffering from esophageal cancer is planned.

More information about the study is available at clinicaltrials.gov (NCT03983954) and at neotx.com.

Phase IIa study in combination with docetaxel in patients with non-small cell lung cancer

Completed

An open label clinical phase IIa study in US testing naptumomab in combination with docetaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) previously treated with checkpoint inhibitors is completed and results were presented at the American Society of Clinical Oncology in June 2024. The primary endpoint of the study is objective response rate.

The trial enrolled 38 patients with NSCLC previously treated with platinum and checkpoint-inhibitor (CPI) therapy. Safety of NAP was acceptable with mostly grade 1-2 infusion related reactions, were generally easily manageable and rapidly reversable.

32 patients were evaluable for response. Five patients had partial response (PR), two of them unconfirmed, and overall response rate (primary endpoint) was 16%. Two patients had prolonged responses: one lasted for 22 months and the second had a complete response lasting for 24 months despite CNS progression. Mean duration of response was 7.3 months (1.3 – 20.8). Mean PFS was 4.6 months, 18 patients (56%) had stable disease, disease-control rate was 72%, with mean duration of 5.3 months.

Median OS was 8 months with 11 patients (34%) still alive at database lock. Pretreatment with obinutuzumab successfully eliminated anti-drug antibodies (ADAs), which enables prolonged naptumomab exposure. In conclusion, the combination of NAP and docetaxel show preliminary evidence of activity but no increase in overall response rate (primary endpoint) compared to docetaxel alone. The safety of the combination was acceptable in these heavily pretreated NSCLC patients.

For more information about the trial, visit clinicaltrials.gov (NCT04880863) and at neotx.com.

Publications

Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading. Meir Azulay, Michal Shahar, Eitan Shany, Eti Elbaz, Sveta Lifshits, Marie Törngren, Adam Friedmann, Robert Kramer & Gunnar Hedlund. Journal of Translational Medicine 2023 21:222. Read the article here.

Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer. Hossein Borghaei, Katherine Alpaugh, Gunnar Hedlund, Göran Forsberg, Corey Langer, Andre Rogatko, Robert Hawkins, Svein Dueland, Ulrik Lassen, Roger B Cohen. J Clin Oncol. 2009 Sep 1; 27 (25): 4116-23.

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