Background Antibody Drug Conjugates (ADCs)
Antibody Drug conjugates (ADCs) combine the principle of targeting cancer cells via tumor-specific antibodies and delivering highly potent cellular toxins to such targeted cancer cells, which are covalently coupled to the tumor specific antibodies. The linkage between the antibody and the toxin should only release the toxin upon binding and/or internalization of the ADC into the cancer cells.
However, the practical realization of this simple concept of targeting cancer cells with highly toxic compounds via tumor-specific antibodies is not trivial.
A whole chain of factors influences the overall success of ADC development:
1.) It starts with the selection of the right target, that ideally should exclusively be expressed on cancer cells and tissue, but which should be absent or expressed at negligible levels on healthy cells or tissues. This key aspect is addressed by NBE-Therapeutics by engaging international academic experts in the ADC target discovery/validation field providing best guidance, which cancer targets may be tractable to ADC approaches.
2.) The quality of the targeting antibody needs to adhere to highest quality standards and should provide the best possible “carrier” molecule with favorable biophysical and functional properties. The long-standing experience of NBE-Therapeutics team in the therapeutic antibody development field and the high quality output of NBE-Therapeutics' proprietary antibody discovery platform Transpo-mAbTM Display, guarantees the selection of targeting antibodies with optimal developability parameters.
3.) The quality of binding of the targeting antibody can have a significant impact on the efficiency of ADC internalization and/or efficiency of target cell killing. NBE-Therapeutics addresses this aspect by integrating functional screens early in the antibody discovery process.
4.) The quality and potency of the toxic payload represents another compounding factor for the successful development of a potent ADC. Here, NBE-Therapeutics has developed its own, ultra-potent toxin platform that allows addressing tumors and cancer cells with comparably low target expression.
5.) Especially in the context of NBE-Therapeutics' ultra-potent toxin payloads, the covalent attachment of the toxin to the antibody is of pivotal importance for a potent and safe ADC. First, the linker has to assure that the ADC exhibits high stability in circulation and does not release its payload before binding to the tumor has occurred. Second, the linker has to allow efficient release of the toxin inside targeted tumor cells. NBE-Therapeutics linkers, which are the result of its proprietary enzymatic SMAC-technology provide exquisite stability and therefore safety of NBE-Therapeutics’ ADCs comprising ultra-potent toxins.
6.) The site of payload conjugation to the antibody and the number or toxins coupled to the antibody also plays an important role in achieving optimal safety and efficacy for an ADC. Conventional, chemically conjugated ADCs, which employ classic maleimide linker chemistry used in the majority of clinical-stage ADCs do neither offer control of the site of conjugation, nor control of the number of drugs conjugated per antibody (the so-called drug-to-antibody ratio, DAR). Stability of conjugations at different amino acid side chains can significantly differ depending on the chemical microenvironment of the conjugation site. Furthermore, over-conjugated ADCs with high DARs have unfavorable properties due to increased hydrophobicity of the payloads that lead to higher propensity for aggregation and clearance of high DAR ADCs from serum. The faster clearance and/or variable de-drugging rates of toxins attached at different conjugation sites add to the non-specific or pre-mature release of the toxin payload in circulation and negatively affects the safety of the ADC drugs. All of these issues are avoided by NBE-Therapeutics proprietary SMAC-technologyTM, which exploits site-specific conjugation of payloads to antibodies by sortase enzymes. Sortase enzymes are transpeptidase protein ligase enzymes that couple toxin payloads with stable peptide linkers to defined sites in the antibody molecule. The manufacturing of NBE-Therapeutics SMAC-technologyTM generated ADCs has been optimized to result in entirely homogeneous, site-specifically conjugated ADCs with uniform biophysical and functional properties.