Current progress and remaining challenges of peptide-drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)?

Abstract

Drug conjugates have emerged as a promising alternative delivery system designed to deliver an ultra-toxic payload directly to the target cancer cells, maximizing therapeutic efficacy while minimizing toxicity. Among these, antibody-drug conjugates (ADCs) have garnered significant attention from both academia and industry due to their great potential for cancer therapy. However, peptide-drug conjugates (PDCs) offer several advantages over ADCs, including more accessible industrial synthesis, versatile functionalization, high tissue penetration, and rapid clearance with low immunotoxicity. These factors position PDCs as up-and-coming drug candidates for future cancer therapy. Despite their potential, PDCs face challenges such as poor pharmacokinetic properties and low bioactivity, which hinder their clinical development. How to design PDCs to meet clinical needs is a big challenge and urgent to resolve. In this review, we first carefully analyzed the general consideration of successful PDC design learning from ADCs. Then, we summarised the basic functions of each component of a PDC construct, comprising of peptides, linkers and payloads. The peptides in PDCs were categorized into three types: tumor targeting peptides, cell penetrating peptide and self-assembling peptide. We then analyzed the potential of these peptides for drug delivery, such as overcoming drug resistance, controlling drug release and improving therapeutic efficacy with reduced non-specific toxicity. To better understand the potential druggability of PDCs, we discussed the pharmacokinetics of PDCs and also briefly introduced the current PDCs in clinical trials. Lastly, we discussed the future perspectives for the successful development of an oncology PDC. This review aimed to provide useful information for better construction of PDCs in future clinical applications.

Keywords: Antibody drug conjugate; Clinical trials; Peptide drug conjugate; Pharmacokinetics; Targeted drug delivery.

Fig. 1

The challenges of ADCs and the chances for PDC in future drug development

Fig. 2

Multifunctional peptides used in PDCs, including cell penetration peptides, tumor targeting peptides, and self-assembling peptides

Fig. 3

Stabilized peptide drug conjugate targeting HDACs for cancer therapy. (A) The design of PDCs targeting HDAC. H3K56 peptide is derived from Histone 3, which is the substrate of HDAC1. The functional group hydroximic acid plays a key role for HDAC binding [107]. (B) Sulfonium-tethered PDCs targeting HDAC with decreased non-specific toxicity [108]. Copyright permission obtained with ref. no.83–84 from the author

Fig. 4

An assembly-inducing PDC deliver nucleic acid for cancer therapy. This PDC consists of the cell penetration peptide RW9, an HDAC inhibitor warhead (peptide C-terminus), and 5-FU (peptide N-terminus), which can coassemble with AS1411 to form nanospheres. This PDC showed unexpected synergy with AS1411 to augment the cancer cell suppression efficiency, exemplified by the downregulation of the stemness-related proteins and the upregulation of apoptosis-related proteins. Copyright permission obtained with ref. no 92 from The Royal Society of Chemistry

Fig. 5

Different linkers used in PDCs. The linkers used in PDCs included cleavable linkers and non-cleavable linkers

Fig. 6

The design of VEGFR targeting peptide conjugate (QR-KLU) and the antineoplastic efficacy of peptide QR-KLU in vitro and in vivo. Peptide QR-KLU is a conjugation of VEGFR targeting peptide VEGF_{125 − 136} (QKRKRKKSRYKS) and a reported lytic peptide(KLUKLUKKLUKLUK). This PDC showed good in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibited angiogenesis in tumor tissues with good safety. Copyright permission obtained with ref. no [55]. from Springer nature

Fig. 7

Three different kinds of PDCs in the future development