Abstract 2497
Background
Frequent over-expression of FRA in ovarian and non-small-cell lung cancer (NSCLC), and relative lack of expression in normal tissue, make it an attractive therapeutic target. Ovarian cancer is the ninth most common cancer in women and the leading cause of death in gynaecological cancer. Lung cancer remains a leading cause of cancer-related death with NSCLC accounting for 80 % of cases. ADCs are the focus of intense interest as a means to provide selective tumor killing with increased efficacy and less off-target toxicity than standard of care chemotherapies. Clinical evaluation of mirvetuximab soravtansine in solid tumor indications demonstrated that FRA can be successfully targeted by an ADC. However, anti-tumor activity appears to be generally limited to patients whose tumors express high levels of FRA. IKS01 is an ADC comprised of an FRA-targeting antibody conjugated via Iksuda’s PermaLink conjugation technology to Femtogenix’s highly potent FGX2-62 payload. FGX2-62 is a pyrridinobenzodiazepine DNA mono-alkylating agent with pM potency in a range of tumor cell lines. IKS01 has been designed to be sufficiently potent to have target-dependent efficacy even in tumors with low or moderate expression of the target antigen.
Methods
IKS01 was generated with a drug to antibody ratio of 2. Efficacy was evaluated in human cell line derived xenograft models with a range of FRA expression, including the choriocarcinoma Jeg-3 model (high expression), the ovarian adenocarcinoma OV-90 model (low expression) and the lung adenocarcinoma NCI-H2110 model (moderate expression). An FRA-targeting benchmark ADC with a format that has shown clinical efficacy was included for comparison.
Results
IKS01 is highly effective in causing tumor regressions in FRA-expressing tumor models at doses that are well tolerated. IKS01 was significantly more active than benchmark ADC in the high FRA-expressing Jeg-3 model and caused complete or near complete regressions in low/moderate FRA-expressing xenograft models where the benchmark ADC showed limited or no activity.
Conclusions
IKS01 shows marked anti-tumor efficacy in pre-clinical models of ovarian and lung cancer, even in models with low or moderate FRA expression.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Iksuda Therapeutics Ltd.
Funding
Iksuda Therapeutics Ltd.
Disclosure
J. Thirlway: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. A. Lodge: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. A. Pelava: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. D.J. Williamson: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. D. Carta: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. M. Al Nakeeb: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. J. Mysliwy: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd. P.J.M. Jackson: Shareholder/Stockholder/Stock options: Femtogenix Ltd. D.E. Thurston: Shareholder/Stockholder/Stock options: Femtogenix Ltd. R.J. Lutz: Shareholder/Stockholder/Stock options: Iksuda Therapeutics Ltd.
Resources from the same session
2831 - Interleukin-6 as a Predictive Marker for Early Response to Induction Chemotherapy in Acute Myeloblastic Leukaemia
Presenter: Salah Khallaf
Session: Poster Display session 1
Resources:
Abstract
6014 - Impact of FLT3-ITD mutation on post-transplant outcome of adult AML is modified by the concomitant NPM1 mutation and pre-transplant remission status: A report from Taiwan Bone Marrow Transplant Registry (TBMTR)
Presenter: Su-peng Yeh
Session: Poster Display session 1
Resources:
Abstract
2914 - Efficacy endpoints studied in clinical trials for early-onset leukaemia
Presenter: Dylan Said
Session: Poster Display session 1
Resources:
Abstract
4691 - High triglyceride is a major risk factor of DIC and differentiation syndrome in acute promyelocytic leukemia
Presenter: Tomohiro Yamakawa
Session: Poster Display session 1
Resources:
Abstract
4395 - DREAMM 4: A Phase I/II single-arm open-label study to explore safety and clinical activity of belantamab mafodotin (GSK2857916) administered in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM)
Presenter: Suzanne Trudel
Session: Poster Display session 1
Resources:
Abstract
2808 - A Phase 1 Study of HMPL-523, a Selective Oral Anti-Spleen Tyrosine Kinase Inhibitor, in Patients with Relapsed or Refractory Lymphoma
Presenter: Nathan Fowler
Session: Poster Display session 1
Resources:
Abstract
4403 - A Phase 1 Study of HMPL-689, a Selective Oral Phosphoinositide 3-Kinase-Delta Inhibitor, in Patients with Relapsed or Refractory Lymphoma
Presenter: Jonathon Cohen
Session: Poster Display session 1
Resources:
Abstract
3357 - A global patient-driven Facebook study in a very rare sarcoma: Health-related quality of life in Epithelioid Hemangioendothelioma (EHE) patients
Presenter: Marije Weidema
Session: Poster Display session 1
Resources:
Abstract
2475 - Qualitative study of patients’ experiences of living with and beyond a soft tissue sarcoma diagnosis: the impact of sarcoma specialist services
Presenter: Ana Martins
Session: Poster Display session 1
Resources:
Abstract
2640 - Health-related quality of life issues of patients affected by desmoid-type fibromatosis; experiences from two countries
Presenter: Milea Timbergen
Session: Poster Display session 1
Resources:
Abstract