The first available data on Iksuda Therapeutics‘ (previously Glythera) lead antibody-drug conjugate, IKS01, has shown significant and effective tumor regression in preclinical models of ovarian and lung tumors.
The investigational agent targets the folate receptor. The data was presented during the European Society for Medical Oncology (ESMO) 2019 Congress, being held in Barcelona, Spain, September 27 – October 1, 2019.
Antibody-drug Conjugates or ADCs allow for the targeted delivery of a potent cytotoxic payload to tumors, resulting in selective killing with increased efficacy and less off-target toxicity than standard-of-care chemotherapy.
Frequent over-expression of FRα in ovarian and non-small-cell lung cancer (accounting for 80% of all lung cancer cases) and relative lack of expression in normal tissue, make it an attractive therapeutic target.
However, anti-tumor activity is generally limited to patients whose tumors express high levels of FRα.
Next-gen antibody-drug conjugates
IKS01 is an antibody-drug conjugate comprised of an FRα-targeting antibody conjugated via Iksuda’s PermaLink® technology to Femtogenix’s highly potent FGX2-62 payload.
The company’s PermaLink-technology is a cysteine-specific, vinyl pyridine-based chemistry that demonstrates inherent conjugation stability and, unlike many other approaches to conjugation, Iksuda’s PermaLink® chemistry is not susceptible to drug de-conjugation.
In vivo experiments with PermaLink-based ADCs demonstrate improved tolerability and overall tumor response. The enhanced stability profile of PermaLink enables the safer use of ultra-potent toxins which, when conjugated to antibodies that are directed to well-selected targets, results in more efficacious ADCs.
FGX-2-62, the payload in Iksuda’s IKS01 antibody-drug conjugate, is a pyridinobenzodiazepines (PDDs), a new class of sequence-selective, DNA mono-alkylating payload which contain a polyheterocyclic chain with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites).
The ultra-potent payload has a different sequence-selectivity profile to other DNA-interactive agents, spanning 8-9 base-pairs compared to 6-7 for a PBD dimer, and DNA footprinting experiments indicate a preference for 5′-XGXWWWWXX-3′ sequences (X is any base; W is A/T).
Transcription factor array studies have shown that FGX2-62 inhibits DNA-binding of oncogenic transcription factors (e.g., NF-κB and GATA).
In in vitro cell line studies, FGX2-62 has low pM cytotoxicity in a diverse cell line panel, including stem cells, cells from both solid and blood cancers (e.g., 9 pM in HL-60) and MDR-resistant tumors, and arrests the cell cycle at the G0/G1 phase compared to G2-M arrest for Pyrrolobenzodiazepines (PBD-) dimers.
Scientists have also confirmed that Femtogenix’s FGX2-62 is compatible with attachment to most linker technologies, and is significantly less hydrophobic than most other payload classes.
IKS01 is target specific and the data presented during the 2019 ESMO Congress confirm that it is highly effective in causing tumor regression in FRα-expressing models at doses that are well-tolerated, significantly more active than a benchmark ADC and caused complete regressions in low/moderate FRα-expressing models.
The IKS01 data is a major advancement of Iksuda’s ADC drug pipeline, from which it aims to progress multiple candidates towards first clinical studies in 2020.
“Ovarian cancer is one of the most deadly gynecological cancers and lung cancer remains a leading cause of cancer-related death. The IKS01 data highlight the potential impact of our ADC pipeline by targeting difficult-to-treat tumors and advancing current standard of care,” noted Dave Simpson Ph.D, Chief Executive Officer of Iksuda Therapeutics.
Veillard N, Andriollo P, Mantaj J, Fox KR, Rahman KM, Procopiou G, Cascio F, et al. Pyridinobenzodiazepines (PDDs): A new class of sequence-selective DNA mono-alkylating ADC payloads with low hydrophobicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 736.