Study Demonstrates Superior Efficacy and Cytotoxicity of Femtogenix’s Sequence-selective DNA-interactive Payload

Featured Image - Laboratory. Courtesy 2019 Fotolia
Featured Image - Laboratory. Courtesy 2019 Fotolia

Data verifying a favorable toxicity profile and potent efficacy of a novel pyrridinobenzodiazepine (PDD) antibody-drug conjugate payload platform in tumor cell models was presented by Professor David Thurston, Ph.D., Chief Scientific Officer of Femtogenix, at the 10th annual World ADC conference being held October 8 – 11, 2019 in San Diego, California. [1]

Antibody-drug conjugates or ADCs are capable of delivering highly cytotoxic payloads directly at the tumor site.

In the development of novel antibody-drug conjugates, medical scientists are looking for maximal efficacy with minimal toxicity. Efforts to design and refine ADC have generally focused on the selectivity of antibodies as well as drug mechanism of action, drug-linking, drug-antibody ratio (DAR) , and drug-releasing properties.[2][3]

Lonza
ADC Bio
MabPlex
 

Some payload classes, including PBD dimers, are notably hydrophobic leading to problems with, for example, aggregation during conjugation. As a result there is interest in developing new payloads which retain the potency of DNA cross-linkers, while, at the same time, having a lower hydrophobicity and, when being apart of an ADC, a wider therapeutic window.[4]

When attached to antibodies or other targeting moieties, Femtogenix’s novel PDD platform allows reversible/irreversible DNA minor groove binding, in a sequence-interactive manner, leading to highly targeted cytoxicity towards tumor cells.

Novel mechanism of action
The payloads are designed to have a novel mechanism of action and IP space compared to existing DNA-interactive payloads, to have minimal hydrophobicity, and to be resistant to P-Glycoprotein pumps in tumor cells.

The new data describe details of Femtogenix’s latest payload molecules for ADC use, and demonstrate that high potency mono-alkylators derived through the PDD platform, contain a polyheterocyclic chain with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites). As a new class of payloads, PDDs have a favorable toxicity profile in rats, coupled with potent in vivo efficacy (sub mg/kg doses) and excellent tolerability (i.e., MTDs > 10 mg/kg) when conjugated to antibodies. [1][4]

Femtogenix’s lead PDD payload, FGX2-62, has a different sequence-selectivity profile to other DNA-interactive agents, spanning 8-9 base-pairs compared to 6-7 for a PBD dimer.

New class of DNA cross-linking payloads
Femtogenix also introduced a new class of DNA cross-linking ADC payloads at the 10th World ADC conference. This class of payloads is based the company’s its proprietary PDD platform and include potent in vivo efficacy and substantially enhanced tolerability profiles compared to competing technologies.

“These data show that our PDD technology overcomes many of the limitations of existing approaches to ADC payloads,” noted Christopher Keightley, Femtogenix’ Chief Executive Officer.

“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,” Keightley added.

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 fluorescence resonance energy transfer (FRET-) studies.1

The molecules have been designed through proprietary molecular modeling methodologies to maximize 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.

More details

Pyrridinobenzodiazepine (PDDs) is a related structure to pyrrolobenzodiazepine (PBD)

Pyrridinobenzodiazepine or PDD is a related structure of pyrrolobenzodiazepine (PBD), a group of compounds that have been shown to be sequence-selective DNA minor-groove binding agents originally discovered in Streptomyces species.[5]

They are essentially tricyclic andconsist of a fused 6-7-5-membered ring containing anthranilate (A ring), diazepine (B ring), and pyrrolidine (C ring). They electrophilic N 10 = C 11 imine groups or equivalent hydrated, carbinolamine [NH-CH (OH)], or carbinolamine alkyl ether [NH-CH (OR characterized by R = alkyl)] in the formula, it, C 2 of guanine in DNA – to form a covalent bond to an amino group can form DNA adducts.[5]

_

Note: 1 FRET-studies are a powerful technique for studying molecular interactions inside living cells with improved spatial (angstrom) and temporal (nanosecond) resolution, distance range, and sensitivity and a broader range of biological applications.

Reference
[1] New Developments with the Pyridinobenzodiazepine (PDD) Payload Platform, presented by Professor David Thurston, Scientific Co-Founder and Chief Scientific Officer, Femtogenix on 11 October 2019, World ADC, as part of the talk ‘What Lies Ahead for ADCs’.
[2] Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008 Aug;26(8):925-32. doi: 10.1038/nbt.1480.
[3] Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, French D, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009 Sep 24;114(13):2721-9. doi: 10.1182/blood-2009-02-205500. Epub 2009 Jul 24.
[4] Veillard N, Andriollo P, Mantaj J, Fox KR, Rahman KM, Procopiou G, Cascio F, Corcoran DB, 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.
[5] International patent application number PCT/GB2016/052565, filed 19 Aug. 2016. Online. Last accessed, October 13, 2019.