Peptide-Drug Conjugates (PDCs) Emerge as Promising Targeted Cancer Therapies
核心洞察
Peptide-drug conjugates (PDCs) are emerging as a novel class of cancer therapeutics, offering potential advantages over antibody-drug conjugates (ADCs) due to their smaller size and rapid internalization.
PDCs targeting SORT1 (搜索), a transmembrane glycoprotein highly expressed in various solid tumors, demonstrate enhanced drug delivery and reduced off-target toxicity in preclinical studies.
Theratechnologies' SORT1 (搜索)+ Technology platform is advancing PDCs, with early clinical data showing durable disease stabilization and a unique mechanism of action in advanced solid tumors (搜索).
As antibody-drug conjugates (ADCs) and immune checkpoint inhibitors continue to advance as cancer therapies, peptide-drug conjugates (PDCs) are emerging as a promising modality, potentially ushering in a new wave of R&D programs. PDCs offer potential advantages over ADCs, including smaller size, rapid internalization, and improved tumor penetration.
The potential of PDCs largely stems from their advantages over ADCs. Despite their success, ADCs’ clinical benefit and duration of objective response are limited by the emergence of resistance mechanisms, their large size, and their relatively long half-life, which can increase the risk of neutropenia, neuropathy, hepatotoxicity, and other off-target effects. Most ADCs are further limited by their slow internalization into the target cell (6 to 14 hours), leaving them on the cell surface for an extended period and reducing the volume of drug that reaches the intracellular target; this limitation necessitates conjugation with highly toxic drugs. Consequently, there remains a demand for precisely targeted therapies with more favorable tolerability profiles and for improved delivery systems that enable safe and effective combination treatments.
PDCs—therapies that use a cleavable or non-cleavable linker to attach a receptor-targeting peptide to a drug payload — appear poised to meet that need. Compared to ADCs, PDCs are small, agile chemical entities, some with half-lives of a few hours and targets that are enabling rapid internalization and improved tumor penetration. Those properties may allow for sustained, robust anticancer activity, an improved safety profile, and conjugation with different payloads. PDCs also appear able to bypass drug resistance mechanisms and enhance immune checkpoint inhibition. Additionally, compared to monoclonal antibodies, PDCs are less expensive to produce, faster to advance from preclinical to clinical development, and offer enhanced tumor penetration as well as greater flexibility in terms of ease of payload-switching.
SORT1: Optimizing Target Selection
Sortilin (SORT1 (搜索)), a transmembrane glycoprotein of the vacuolar protein sorting 10 protein (Vsp10p) family, exemplifies the promise of PDC therapy. SORT1 normally functions as a cellular shuttle system to transport proteins across the cell membrane and to rapidly internalize them via the endosomal/lysosomal pathway. SORT1 is highly expressed in many solid tumors, including ovarian, endometrial, and breast cancers, and is associated with tumorigenesis, resistance, progression, advanced disease, poor prognosis, and reduced survival outcomes in cancer. Its attractiveness as a research target is further enhanced by its higher expression in cancer cells compared to normal cells.
SORT1 (搜索)-targeting PDC therapy leverages the natural internalization function of SORT1 to promote rapid internalization and delivery of a cytotoxic payload directly into cancer cells, while limiting ligand degradation in the circulation as well as off-target toxicity. By rapidly internalizing its natural ligands (e.g., progranulin, neurotensin), and with a half-life of 4 minutes, SORT1 expedites peptide uptake within cancer cells.
Evidence of the Viability of PDCs in Anticancer Therapy
Theratechnologies has established the SORT1 (搜索)+ Technology™ platform as an engine for the development of PDCs that target SORT1. The platform relies on the use of a novel, proprietary peptide called TH19P01, which can be conjugated to numerous well-characterized anticancer drugs.
Preclinical data presented earlier this year at the American Association for Cancer Research (AACR) annual meeting demonstrated that investigational camptothecin-peptide conjugates are well tolerated and associated with significant tumor regression in colorectal cancer (搜索) (CRC) xenograft models. In one experiment, SORT1 (搜索) gene silencing inhibited camptothecin-conjugate uptake in human HT-29 colorectal adenocarcinoma cells, suggesting that these PDCs enter cancer cells via a SORT-1 mediated internalization process. In other experiments, three PDCs – TH2101, TH2205, and TH2310 – that carry a cytotoxic payload of SN-38, the active metabolite of irinotecan, exerted greater anti-proliferative activities against CRC cells in mice, compared to unconjugated irinotecan. In two different CRC xenograft models, as well as in a triple-negative breast cancer (搜索) (TNBC) xenograft model, a fourth PDC, TH2303, which carries an exatecan payload, was associated with increased tumor growth inhibition and greater tolerability compared to unconjugated exatecan or irinotecan.
Additionally, the combination of two SORT1 (搜索)-targeting PDCs – sudocetaxel zendusortide and TH2101, which have a synergistic anti-tumor effect at reduced doses – led to increased tumor growth inhibition and some complete responses in the HT-29 xenograft model, compared to either PDC administered alone; the combination also was well tolerated. The significant tumor regression following combination therapy is notable because the HT-29 xenograft model is notorious for its resistance to multiple cytotoxic drugs.
More than 50 patients with advanced solid tumors (搜索) have been dosed with sudocetaxel zendusortide (TH1902) as part of a Phase 1 clinical trial in multiple tumor types. An updated analysis from Parts 1 and 2 of the trial, presented at the 2024 American Society of Clinical Oncology (ASCO) annual meeting, showed that sudocetaxel zendusortide induced durable disease stabilization (up to 45 weeks) lasting beyond treatment completion. Results suggest a unique, multimodal mechanism of action distinct from other cancer therapeutics, including induction of immune cell infiltration even in “cold” tumor models, inhibition of vasculogenic mimicry, targeting of chemotherapy-resistant cancer stem cells, and activation of the cGAS/STING immune pathway, among other actions. Part 3 of the Phase 1 trial is currently underway in patients with advanced ovarian cancer (搜索).
A Potential Profusion of Conjugates Including Radioisotopes
The versatility of the SORT1 (搜索)+ Technology™ platform may enable development of follow-on conjugates that take advantage of the internalization properties of the SORT1 receptor. In particular, those properties appear to make SORT1 a suitable target for radioisotope conjugates, in that the receptor’s ability to promote rapid internalization would appear to facilitate entry of a radioisotope into target tumor cells while limiting impact on other, non-cancerous tissues.
Radioisotopes are just one example of the kinds of next-generation conjugates that could emerge from SORT1 (搜索)-directed research efforts and potential development partnerships leveraging our PDC platform. The utility of conjugate-based anticancer therapy is spurring opportunities for collaboration between biotechnology and pharmaceutical companies both large and small, with some companies basing their entire pipelines on such models.
Those possibilities have made PDCs and their follow-on compounds a category to watch.