French biotech company Diaccurate, specialized in the development of new therapies in oncology, has received from grant from the Banque publique d’investissement (Bpifrance), a French public investment bank, to help the company fund its DIACC2020 Program.  The Aide à l’Innovation will help Diaccurate to establish preclinical proof-of-concept of its first-in-class molecule, DIACC2010, as a next-generation payload for antibody-drug conjugates (ADCs) for the treatment of solid and hematologic tumors.

Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody directed towards a tumoral target, coupled with a molecular linker to a potent cytotoxic drug. ADCs selectively deliver inside tumor cells the conjugated chemotherapy, improving its efficacy and tolerability profiles.

ADCs are effectively used for the treatment of numerous cancers. However, the high toxicity of these agents, for a large part mirroring that of their conjugated anticancer agent, limits their therapeutic index and clinical use.

Targeting KIF20A
DIACC2010 is a first-in-class small molecule targeting the microtubule associated motor protein KIF20A (also called MKlp2), a novel oncology target discovered in collaboration with ICSN/CNRS.[1]

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KIF20A, a member of the kinesin-6 family, plays an essential role during cytokinesis and is, in addition, involved in the fission of RAB6-positive vesicles from Golgi apparatus and the control of cell division, therefore contributing to intracellular vesicular trafficking.[1][2]

KIF20A plays a critical role in the development and progression of many cancers. Studies have show that immature hematopoietic cells exhibit high KIF20A expression, whereas mature peripheral blood cells do not. In turn, high expression of KIF20A is associated with disease progression and poor survival outcome. [3][4]

DIACC2010
Preclinical studies DIACC2010 demonstrated potent and consistent cytotoxic activity in vitro against a panel of 9 human AML cell lines, with median IC50 of 40 nM (range 10-77 nM). In the same experimental conditions, cytarabine (Cytosar-U®; Pfizer/Hospira), a pyrimidine analog also known as arabinosylcytosine or ARA-C, had median IC50 of 207 nM (range 4-1580 nM).

DIACC2010 was subsequently evaluated in vivo in xenograft models of AML cell lines. The results demonstrated that DIACC2010 significantly improved overall survival as compared to ARA-C in all models, with dose-dependent efficacy

These initial outcomes confirmed that DIACC2010 is a potent preclinical anti-tumor efficacy in aggressive models of Acute Myeloid Leukemia and solid tumors, including breast cancer. Its efficacy profile together with the lack of toxicity towards normal cells strongly support the evaluation of DIACC2010 conjugated to therapeutic antibodies, for the development of a new generation of optimized ADCs.

More efficacious – better tolerated
In preclinical tumor models, the DIACC2020 Program, which is supported by Bpifrance, is expected to demonstrate, that antibody-drug conjugates with a DIACC2010 payload are more efficacious and better tolerated than their referent ADC counterparts, thus improving their therapeutic index and broaden their potential indications.

The workplan will run for 18 months up to the preclinical proof-of-concept in at least two models of human tumors. Preliminary efficacy and toxicity results will be available by the end of 2023 and will support potential license agreements with pharmaceutical companies.

Highlights of prescribing information
Cytarabine (Cytosar-U®; Pfizer/Hospira) [Prescribing information]

Reference
[1] Garciaz S, Collette Y, Castellano R, Aurrand-Lions M, Sicard H, Jentreau L, Vey N, Bougeret C. DIACC2010, Sole-in-Class Selective Inhibitor of Kinesin KIF20A, Has Potent Preclinical Efficacy in Acute Myeloid Leukemia. Blood 2022; 140 (Supplement 1): 7800–7801. doi: https://doi.org/10.1182/blood-2022-166820
[2] Miserey-Lenkei S, Bousquet H, Pylypenko O, Bardin S, Dimitrov A, Bressanelli G, Bonifay R, Fraisier V, Guillou C, Bougeret C, Houdusse A, Echard A, Goud B. Coupling fission and exit of RAB6 vesicles at Golgi hotspots through kinesin-myosin interactions. Nat Commun. 2017 Nov 1;8(1):1254. doi: 10.1038/s41467-017-01266-0. PMID: 29093437; PMCID: PMC5665954.
[3] Li X, Shu K, Wang Z, Ding D. Prognostic significance of KIF2A and KIF20A expression in human cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2019 Nov;98(46):e18040. doi: 10.1097/MD.0000000000018040. PMID: 31725680; PMCID: PMC6867763.
[4] Morita H, Matsuoka A, Kida JI, Tabata H, Tohyama K, Tohyama Y. KIF20A, highly expressed in immature hematopoietic cells, supports the growth of HL60 cell line. Int J Hematol. 2018 Dec;108(6):607-614. doi: 10.1007/s12185-018-2527-y. Epub 2018 Sep 4. PMID: 30182171.

Featured Image: Researchers in laboratory  Courtesy: © 2017 – 2023. Fotolia/Adobe. Used with permission.

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