NBE-Therapeutics' ultra-potent anthracycline based toxin platform
In addition to NBE-Therapeutics' Transpo-mAbTM Display antibody discovery and SMAC-TechnologyTM for enzymatic site-specific conjugation of toxic payloads to antibodies, NBE-Therapeutics has also developed an ultra-potent toxin platform that is proprietary in the context of SMAC-TechnologyTM manufactured ADCs. The majority of ADCs currently in clinical development, and the two FDA-approved ADC products Adcetris® and Kadcyla®, comprise tubulin-polymerization inhibiting toxins related to maytansine or mono-methylauristatin toxins, which were developed by Immunogen and Seattle Genetics, respectively. These agents act particularly on proliferating cells, which need to re-organize their tubulin cytoskeleton in the context of mitosis and cell division. However, due to the abundance of the cellular target tubulin, these drugs need to internalize into the cytoplasm of cells in relatively high concentrations, and cancer targets expressed a low levels and/or with reduced internalization rate are often not tractable to maytansine and mono-methylauristatin based ADCs. Therefore, more potent, particularly DNA-damaging and intercalating toxins, like pyrrolo-benzodiazepines (PBDs) or duocarmycines have become more popular, because it was found that ADCs with such DNA damaging toxins are more potent than maytansine and mono-methylauristatin versions of the same ADCs.
At NBE-Therapeutics, we are leveraging a highly potent anthracycline-based DNA-intercalating toxin that is related to the established cancer drug doxorubicine, and which has been termed PNU-159682. It has been reported in the literature that the PNU-159682 anthracycline is up to 5000x more potent on selected cancer cell lines than the standard doxorubicine toxin. Such ultra-potent toxins require highly stable linkers that covalently attach the toxin to the antibody and a defined conjugation site with uniform stability is almost a crucial requirement. We have established that this ultrapotent toxin, modified via a stable amide and peptide bond linker, can be coupled very efficiently to the C-termini of antibody heavy and light chains using NBE-Therapeutics SMAC-TechnologyTM. In this context, on one hand high serum and plasma stabilities are achieved, while at the same time maintaining high potency of ADCs with this toxin.
Furthermore, recent publications suggest that the PNU-toxin is not a substrate for the multidrug resistance pump P-gp, that acts on tubulin-polymerization inhibitors and other toxins, thereby reducing their efficacy.
Lastly, early experiments with PNU ADCs using immune-competent mouse cancer models suggest that the ADCs comprising the PNU-toxin payload elicit an immunogenic cell death (ICD), resulting in a long-lasting and permanent eradication of xeno-transplanted tumors. This even results in immune-protection against re-challenge with the same tumor. An immune stimulatory function of anthracycline toxins is known form the literature and is in full support of these findings.
- Ultra-potent anthracycline based DNA-intercalating toxin platform
- High serum stability of SMAC-TechnologyTM manufactured ADCs
- Toxin is not a substrate for P-gp multidrug efflux pump
- Indication of immune-oncology function of ADCs comprising PNU-toxin payload
- No apparent toxicity of ADCs at effective dose of 1 mg/kg in mouse tumor models