RE:RE:To better understand the complexity of ADCsNow the advantages of peptides as drug carriers.
Most of these drawbacks can be eliminated by using smaller biomolecules like peptides. In fact, peptide-drug conjugates (PDC) comprise several advantages as carrier molecules. Peptides with up to 50 amino acids can be easily synthesized in large scale to a reasonable price and modifications as non-natural amino acids can be directly introduced in the synthesis process (Firer and Gellerman, 2012; Mde et al., 2014). The straightforward synthesis allows a rational optimization of side chains and backbone structures, which can result in increased binding affinities and physicochemical properties can be directly influenced (Erak et al., 2018). Furthermore, peptides are considered to be rapidly cleaved by proteolytic enzymes and quickly cleared from the blood circulation by liver and kidney. Those pharmacodynamic properties can be modulated by different modification and stabilization approaches (Vlieghe et al., 2010). One of the most known concepts of peptide stabilization is lipidation, which involves the incorporation of fatty acids into the peptide (Zhang and Bulaj, 2012). Fatty acids bind to serum albumin, preventing proteolytic cleavage in the blood by proteases and leads thereby to a prolonged circulation time (Frokjaer and Otzen, 2005). The long-acting glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide (Victoza®) (Guryanov et al., 2016) and semaglutide (Ozempic®) (Marso et al., 2016), which are used to treat type-2 diabetes and obesity, are recent examples for this approach. Peptides are generally considered safe, since they feature low immunogenicity and produce non-toxic metabolites (Ahrens et al., 2012). Furthermore, their low molecular weight leads to an enhanced penetration into solid tissues resulting in better anti-tumor effects (Firer and Gellerman, 2012; Hock et al., 2015).
Peptides used in PDCs can be divided into two categories: cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs). The uptake mechanisms of CPPs across the cell membrane are not fully understood yet. Some CPPs are reported to cross the cell membrane by an energy-dependent cellular process like endocytosis- or receptor-mediated uptake, whereas others use energy-independent non-endocytic translocation pathways (Derossi et al., 1996; Thorn et al., 2005). Nevertheless, a significant increase in drug delivery was reported for small toxophores as well as for proteins being attached to CPPs like the TAT peptide, Pep-1 or Transportan (Morris et al., 2001; Muratovska and Eccles, 2004; Duong and Yung, 2013). However, extensive application of CPPs is limited due to its low cell specificity (Regberg et al., 2012).
In contrast, CTPs are ideal carrier molecules as they possess the same ability as mAbs. They bind with high affinity to overexpressed receptors on the tumor cell surface without exhibiting the disadvantages of mAbs. However, the conjugation of payloads to the peptide molecules is more critical because receptor binding and selectivity can be affected due to the steric demand of the payload, which can interfere with receptor recognition. Therefore, extensive knowledge of the interaction between peptide and receptor is needed to introduce drug cargos rationally. Amino acids like lysine, cysteine, glutamate, serine, which are not involved in the receptor recognition, can be used directly for payload conjugation at the sidechain or not required positions can be exchanged by those to introduce possible modification sites (Mde et al., 2014). Many peptides also allow simple N-terminal modification because their N-terminus is not involved in the receptor recognition. Ideally, peptide carriers contain multiple modification sides, which allow the incorporation of multiple payloads per peptide molecule. The increased payload loading can enhance the therapeutic effects due to the increased drug concentrations at the tumor site (Dubowchik et al., 2002; Bhme et al., 2016).
jfm1330 wrote: Back to serious stuff. I am now reading a good article on PDCs. I have not yet finished to read it, but this part is interesting, since again, they compare PDCs to ADCs:
Although these conjugates reached the market and proved the feasibility of this approach, antibodies have serious limitations. Most mAbs do not penetrate into tumors. With a molecular weight of about 150 kDa, they are too big to diffuse efficiently into malignant tissue (Dreher et al., 2006; Jain and Stylianopoulos, 2010). Monoclonal antibodies can be immunogenic, even when they have been humanized and they tend to aggregate in excretory organs like liver and kidneys (Borsi et al., 2002; van Schouwenburg et al., 2010; Carrasco-Triguero et al., 2013). Moreover, the generation of mAbs is very expensive as well as time-consuming and non-selective payload conjugation can lead to reduced product homogeneity (Nejadmoghaddam et al., 2019).
Most of these drawbacks can be eliminated by using smaller biomolecules like peptides.
jfm1330 wrote: Really great article. ADCs are a much more complex matter than I thought and more complexity means more possibilities for something to go wrong. It is quite technical, some understanding of biochemistry is necessary to understand the essence of what is explained in there. After reading that I am more convinced that a good peptide drug conjugate can be better than ADC, but it need to be good, good peptide, good linker and good target. That being said, ADCs and PDCs faced some shared challenges an that make this read interesting to identify and understand some of the potential problems that could be encountered by Thera's PDC. It is not a slam dunk at all.
https://ascopubs.org/doi/10.1200/EDBK_281103