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Targeting tough tumors
HARPENDEN, U.K.—Femtogenix Ltd., a biotechnology company developing DNA-interactive antibody-drug conjugate (ADC) payloads, has presented data on ADCs with reduced potency payloads that have the potential to be safe and effective on difficult-to-treat solid tumors.
Data from a reduced-potency, sequence-selective DNA mono-alkylator analogue from the company’s pyridinobenzodiazepine (PDD) ADC payload platform in solid tumor models demonstrate potent efficacy and a favorable toxicity profile. According to Femtogenix, this represents a promising new approach in ADC development, specifically for the treatment of solid tumor malignancies. The data were presented at AACR-NCI-EORTC International Conference on Molecular Targets & Cancer Therapeutics in Boston in October.
When attached to antibodies or other targeting moieties, the PDD payload platform enables reversible/irreversible DNA minor groove binding, in a sequence-interactive manner. This property results in highly targeted cytoxicity towards tumor cells, the company said. Payloads are designed to have a novel mechanism of action and intellectual property space as compared to existing DNA-interactive payloads, to have minimal hydrophobicity and to be resistant to P-Glycoprotein pumps in tumor cells. These data show that Femtogenix’s reduced potency payload has a favorable toxicity profile in rats, potent in-vivo efficacy (MED < 1 mg/kg) and improved tolerability (i.e., MTD of 40 mg/kg) in solid tumor models when conjugated to antibodies. The platform’s toxicity profile and wide therapeutic window are combined with the ability to increase drug-antibody ratio beyond the traditional limit for increased conjugation to antibodies.
According to Prof. David Thurston, chief scientific officer of Femtogenix, “The favorable hydrophobicity profile of the low potency mono-alkylator and its ease of conjugation, along with the significant in-vivo efficacy and tolerability of the ADCs produced, suggest that this payload represents a promising new approach in ADC development, specifically for the treatment of solid tumor malignancies.”
Femtogenix has generated extensive data on mechanism of action of the ADC payload, illustrating a primary mechanism of action DNA alkylation, combined with an ability to inhibit transcription factors. The molecules have been designed through proprietary molecular modeling methodologies to maximize interaction within the DNA minor groove. Researchers believe that payloads with different potencies and modes of action might be used for specific target situations.
The announcement followed data presented earlier at World ADC 2019, San Diego, verifying the favorable toxicity profile and potent efficacy of Femtogenix’s PDD ADC payload platform in tumor cell models. The studies demonstrated the efficacy and cytotoxicity of the sequence-selective DNA-interactive payload molecules toward tumor cells. At World ADC, Femtogenix described details of its latest payload molecules for ADC use and demonstrate that high potency mono-alkylators derived through the PDD platform have a favorable toxicity profile in rats, combined with potent in-vivo efficacy (sub mg/kg doses) and excellent tolerability (i.e., MTDs > 10 mg/kg) when conjugated to antibodies. Femtogenix also introduced a new class of DNA cross-linking ADC payloads at the World ADC conference, based on its proprietary PDD platform, with potent in-vivo efficacy and substantially enhanced tolerability profiles compared to competing technologies.
According to Dr. Christopher Keightley, CEO of Femtogenix, “These data show that our PDD technology overcomes many of the limitations of existing approaches to ADC payloads. The toxicity profile and ease of conjugation of the PDD mono-alkylators, along with their novel mechanism of action and significant in-vitro and in-vivo efficacy, suggest they represent a promising new payload class. We are delighted with the progress as we conclude significant collaborations with pharma partners who will help us achieve the practical application of our innovative approach to a new generation of ADCs.”
Using a variety of biophysical techniques, including DNA footprinting and FRET studies, Femtogenix has generated extensive data on the specific interaction of these payload molecules with DNA. The molecules have been designed through proprietary molecular modeling methodologies to maximize interaction within the DNA minor groove. The design methodology, which has led to the creation of molecules with a range of potencies, 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 applicable to particular uses or specific target situations.