EVX-020, Sole-in-class KIF20A inhibitor - Next generation ADC payload
A selective KIF20A inhibitor to tackle highly proliferative cancers
By combining the great efficacy and broad therapeutic scope of chemotherapy and the safety potential of targeted therapy, the KIF20A inhibitor EVX-020 (formerly DIACC2010) brings chemotherapy in the era of precision medicine. Non-clinical efficacy was established in acute myeloid leukemia models.
Paving the way for Next generation Antibody-Drug Conjugates (ADC)
Uncontrolled cell proliferation is the “hallmark” of cancers. Thus, antimitotic agents (such as taxanes or vinca alkaloids that hinder the dynamic of microtubules, the intracellular engine that controls cell division and shape) have been successfully used for decade in the treatment of solid and blood cancers but they remain highly toxicity, calling for the development of alternatives approaches to block cell division.
Targeting kinesins has emerged as one such alternative. This family of motor proteins convert the energy stored in ATP into mechanical work. Involved in cell division, some of them (KSP or CENPE) have been subject to the development of inhibitors, but these efforts have thus far remained unfruitful due to low efficacy of the resulting drugs. Given its unique profile and data from in vitro and in vivo studies, EVX-020 could change the game, paving the way for Next generation Antibody-Drug Conjugates (ADC) with EVX-020 as payload.
The KIF20A kinesin acts on cell division and intracellular trafficking
The microtubule associated motor protein KIF20A (previously called MKLP2) plays a key role in cell division but also within the Golgi apparatus (the cell’s “traffic center”) where it is responsible for forming and initiating the transport of secretion vesicles to the cell surface, a mechanism that is essential to ensure the secretion of molecules that promote the growth and migration of cancer cells. Thus, in the absence of KIF20A, the growth of pancreatic cancer cells is significantly inhibited.
KIF20A is overexpressed in many cancers and this dysregulation is associated with disease progression and poor survival outcome. Thus, unlike chemotherapies, KIF20A inhibition should specifically affect cancer cells and spare healthy cells.
The KIF20A inhibitor EVX-020: a sole-in-class selective KIF20A inhibitor
Originally identified in partnership with the discoverers of anti-tubulin agents docetaxel and vinorelbine (ICSN, CNRS, Paris Saclay University), EVX-020 is a small molecule that selectively inhibits KIF20A, while preserving the activity of other related kinesins. After turning KIF20A off:
Cytokinesis, the last step of mitosis (when the two daughter cells become physically separated) is also blocked. Inhibition of KIF20A leads to multinucleated cells and mitotic arrest.
Secretion from the Golgi apparatus is blocked, preventing the release of newly synthezised proteins, essential for cancer progression and metastasis. Furthermore, Golgi body progressively fragments, which leads to cancer cell death.
Figure 1: the dual mode of action of EVX-020
E-Poster presented at AACR2022
EVX-020 exhibits high in vitro cytotoxic activity against a very large number of human cancer cell lines, including Acute Myeloid Leukemia (AML) cell lines. In AML, EVX-020 is also active against cell lines resistant to the standard of care, cytarabine. In vivo, EVX-020 significantly increases the survival of mice implanted with AML cell lines (MOLM-14, U-937, HL-60), in a dose-dependent manner. All these preclinical data demonstrate that EVX-020 has a very high efficacy profile in AML .
Preliminary preclinical studies also indicate that EVX-020 has a promising efficacy profile in solid tumors, especially in pancreatic cancer and breast carcinoma. Improving the efficacy of EVX-020 could be achieved through an increased bioavailability.
Poster presented at ASH 2022
KIF20A inhibitor as novel payload class for ADCs
Antibody–drug conjugates (ADCs) are becoming increasingly prominent in the oncology landscape. Thirteen ADCs are marketed worldwide in solid and blood cancers and more than 100 drug candidates are currently being evaluated in clinical trials. While linker and conjugation technologies have meaningfully improved over time only 6 payloads are used at commercial stage. New payload generation development is the next key success factor in this area.
The KIF20A inhibitor is a potent, selective and safe molecule that fits ideally as a new payload candidate. Through the EVX-020 program, the company intends to validate its potential in the field. In the medium term, these developments will lead to partnerships with specialized companies.
After having successfully completed the feasibility of conjugation and drug release with a conventional peptidic cleavable linker, the company has filed a first patent in mid-2022. Assessment of preclinical efficacy of ADC containing EVX-020 as payload is ongoing, supported by innovation grant from Bpifrance, aiming to demonstrate superior efficacy and improved therapeutic index, as compared to marketed ADCs.