WELWYN GARDEN CITY, United Kingdom, and CHICAGO, April 12, 2018 /PRNewswire/ — Femtogenix, Ltd, a UK biotechnology company pioneering the next generation of DNA-interactive Antibody Drug Conjugate (ADC) payloads, today announced it will present data highlighting the high potency of its new generation of DNA binders for ADCs at the American Association for Cancer Research (AACR) Annual Meeting 2018. AACR 2018 is being held April 14-18, 2018, in Chicago, IL.
A presentation on April 15 will discuss details of Femtogenix’s latest payload molecules for Antibody-Drug Conjugate use.1 The presentation demonstrates that the payloads have exquisite in vitro cytotoxicity (i.e., low picomolar) in a range of tumour cell lines, and when conjugated to antibodies the resulting ADCs have potent anticancer activity in human tumour xenograft studies. In these models, ADCs containing the new payloads were able to achieve complete eradication of the tumour cells, often with only a single dosing.
Femtogenix has been preparing these new payload molecules based on its proprietary Pyridinobenzodiazepine (PDD) platform, members of which exhibit exceptional anti-tumour potency (i.e., femto to low picomolar activity in vitro). The PDD moieties are linked to sequence recognition components that bind non-covalently to DNA, conferring sequence selectivity and allowing the targeting of specific DNA sequences including transcription factor sites that are important in the growth of cancer cells.
Dr Christopher Keightley, Chief Executive Officer of Femtogenix, commented, “Data we are presenting at AACR show that our PDD platform technology overcomes many of the limitations of existing approaches to ADC payloads. The favourable hydrophobicity profile of the PDDs and ease of conjugation, along with their novel mechanism of action, significant cytotoxicity in vitro, efficacy in vivo and tolerability in studies to date suggest they represent a promising new class of payloads. We are already working with a number of partners to make state-of-the-art ADCs under license and look forward to adding others as we make this powerful and versatile new technology widely available to ADC drug developers.”
Femtogenix has generated extensive data on the specific interaction of these payload molecules with DNA using a variety of biophysical techniques including DNA footprinting and FRET studies. The molecules have been specifically designed through proprietary molecular modelling methodologies to maximise interaction within the DNA minor groove. The design methodology has led to the creation of molecules with a range of potencies and has also been used to generate novel DNA cross-linking payloads that form unique DNA adduct structures with differing modes of action. Payloads with differing potencies and modes of action may be suitable for particular uses or specific target situations.
Overall, the novel payloads have improved hydrophilicity over more conventional DNA binding agents, thus facilitating antibody conjugation. The structure of these new payloads also permits a variety of linker attachment sites, providing for ready conjugation to targeting moieties such as antibodies. These novel payloads have already been incorporated into ADCs that have proven highly effective in preclinical studies.
A second Femtogenix presentation reports on a new method developed by Femtogenix scientists to allow the physiochemical properties and hydrophobicity of Antibody-Drug Conjugate payloads to be evaluated and optimized at an early stage of development.2
1 – PO.ET01.01 – Antibody-Drug Conjugates: Agents and Technology, April 15, 1:00-5:00pm, 736 / 3 – Pyridinobenzodiazepines (PDDs): A new class of sequence-selective DNA mono-alkylating ADC payloads with low hydrophobicity, N Veillard, P Andriollo, J Mantaj, KR Fox, KM Rahman, G Procopiou, F Cascio, DB Corcoran, I Pysz, PA Cooper, SD Shnyder, Y Ju, E Tan, WM Schopperle, PJM Jackson, DE Thurston
2 – PO.ET01.01 – Antibody-Drug Conjugates: Agents and Technology, April 15, 1:00-5: 00 pm, 738 / 5 – Development of an HPLC method for the assessment of hydrophobicity of ADC payloads, I Pysz, PJ M Jackson, KM Rahman, DE Thurston.
Femtogenix discovers and develops next-generation DNA-interactive payload molecules for use in antibody drug conjugates (ADCs). Its payloads are designed using a proprietary development platform combining computational chemistry techniques and know-how gained from decades of experience in DNA-targeted drug discovery and development. This unique platform enables Femtogenix researchers to design molecules capable of binding reversibly and/or irreversibly to DNA in a sequence-interactive manner, resulting in exquisite tumour cell cytotoxicity. When attached to antibodies or other targeting moieties, these potent cytotoxic agents can be delivered directly to tumours with minimal systemic toxicities. Based in Welwyn Garden City in the UK, Femtogenix works with a variety of partners to produce novel ADC anticancer agents.