Membrane Hsp70: Novel Biomarker
Heat shock protein 70 (Hsp70) is a chaperone protein produced intracellularly by cells in response to exposure to stressful physiological conditions. Hsp70 has been discovered to be highly expressed on the cell membrane (mHsp70) of a variety of different cancer types, but not expressed highly on normal cells.
Metastatic cancers have the highest membrane Hsp70. Metastatic tumors are responsible for ~90% of cancer-related deaths. Radiation and chemotherapy increases mHsp70 expression and renders tumors more sensitive to therapeutics targeting mHsp70.
Alphageneron has entered into an exclusive worldwide license with Multimmune GmbH of Munich, Germany for its therapeutic and diagnostic technology targeting membrane Hsp70.
Completed Clinical Trials
Phase I Clinical Trial: A Phase I Clinical trial with ENKASTIM NK cell therapy after radio-chemotherapy in patients with metastatic colorectal cancer and non-small cell lung cancer (NSCLC) was completed in Germany, and met safety and tolerability endpoints.
Phase IIa Clinical (Randomized, Controlled) Trial: A Phase IIa (randomized controlled) multi-centre clinical trial with ENKASTIM NK cell therapy in patients with Stage IIIb inoperable squamous NSCLC receiving standard of care radiochemotherapy was completed and showed promising signs of efficacy. In this study, patients were identified as having tumors expressing mHsp70 using an assay which detects levels of exosome-associated Hsp70 in the blood.
Phase IIa Clinical Trial: We are planning a Phase II Clinical Trial of ANKASTIM in combination with PD-(L)1 checkpoint inhibitors in metastatic colorectal cancer. Colorectal cancer is the 3rd leading cause of cancer deaths.
Phase IIa Pivotal Combination Trial: We plan to initiate a Phase IIb/III ‘ ‘Pivotal’ Clinical Trial of ENKASTIM in combination with a PD-(L)1 checkpoint inhibitor in patients with advanced Stage III and Stage IV NSCLC. Lung cancer is the leading cause of cancer deaths, with 85% of lung cancers being NSCLC.
An autologous mHsp70 targeted NK Cell Therapy that activates NK cells to target and kill cells expressing mHsp70. The therapy begins with selecting patients whom have high mHsp70 expression with our Companion Diagnostic AP-CDx (described below), collecting their peripheral blood mononuclear cells (PBMCs) by leukapheresis, ex vivo activation of PBMCs with our synthetic Hsp70-derived peptide (‘TKD’) and low-dose interleukin-2 (IL-2), reinfused intravenously back to the patient. Clinical trials with ENKASTIM autologous NK Cell therapy have been completed or being planned, as follows:
- Completed Phase I clinical trial involving twelve (12) patients in Germany, eleven (11) with metastatic colorectal cancer and one (1) with non small lung cancer (NSCLC) receiving ENKASTIM after standard of care (SOC). The therapy showed it was safe, well tolerated and had signs of efficacy.
- Completed Phase IIa (randomized, controlled) clinical trial involving fourteen (14) patients with advanced (Stage IIIb) NSCLC in Germany, divided into a treated group of seven (7) patients whom received ENKASTIM after radio-chemotherapy, where five (5) patients experienced a clinical benefit (71%), including one complete response (CR) and one partial response (PR); while in the control group of seven (7) patients, only two had a clinical benefit, no patient had a CR. In the ENKASTIM treated group, one patient subsequently received OPDIVO® (nivolumab), achieved 33 months Progressive Free Survival (PFS), in comparison to median nine (9) months survival with OPDIVO® after radio-chemotherapy historical control.
- Planned Phase IIa Clinical Combination trial. Patients with advanced (Stage III & IV) NSCLC, in the United States who have failed standard of care (radio)chemotherapy / PD(L)-1 checkpoint inhibitor therapy will receive ENKASTIM plus standard of care. If the clinical trial shows the therapy is effective, a Pivotal Phase IIb trial will be planned for accelerated approval.
An allogenic NK cell therapy that targets tumors expressing mHsp70. Patients are selected with high mHsp70 exosomes in their blood using our Companion Diagnostic AP-CDx (described below). We obtain PBMCs from healthy donors by apheresis, their NK cells are expanded, and incubated ex vivo with TKD and IL-2, followed by freezing, thawing and intravenous administration to patients.
- Pre-clinical (animal) studies in Germany have demonstrated that TKD/IL-2 activated human allogeneic NK cells control the growth of human metastatic colorectal cancer, NSCLC, and metastatic pancreatic cancer in immune deficient mice. Pre-clinical studies in immune deficient mice have also shown the efficacy of ANKASTIM against human metastatic lung cancer to be further improved when combined with OPDIVO®.
- Planned Phase I clinical Combination trial in metastatic gastric and colorectal cancer (Stage IV) in the United States, after standard of care (SOC) combined with PD(L)-1 checkpoint inhibitor patients, who failed chemo-radiation and PD(L)-1 checkpoint inhibitors as salvage therapy.
Chimeric Antigen Receptor (CAR) NK Cells: Alphageneron is developing ‘off-the- shelf’ umbilical cord (UC) blood- and induced pluripotent stem cell (iPSC)-derived CAR-engineered NK (CAR NK) cell-based cancer therapeutics that target tumors expressing mHsp70, and other (undisclosed) targets. Gene editing of allogeneic CAR NK cells will be used to improve persistence, potency, and efficacy.
Antibody-Based Immune Cell Engagers
Alphageneron is developing multi-specific Immune Cell Engager Therapeutics targeting tumors expressing mHsp70 (currently in pre-clinical development).
Antibody Drug Conjugates (ADCs)
We are also developing an Antibody Drug Conjugates (ADCs) that targets cells expressing mHsp70. Such drugs can be used as a “magic bullet” to deliver a cytotoxic conjugate directly to the large proportion of tumor entities that express mHsp70.
Companion Diagnostic (CDx)
Identifying patients having disease-specific therapeutic targets with a Companion Diagnostic (CDx) dramatically improves outcomes, even in difficult-to-treat disease indications. Tumors expressing mHsp70 cells actively release Hsp70 in exosome-like lipid vesicles.