Peptide-Drug Conjugation (PDC)

Peptide-Drug Conjugation (PDC)

As a leading CRO, BOC Sciences has been supporting customers at the forefront of drug conjugation. Peptide-drug conjugate (PDC) is an emerging promising class of targeted therapeutics. We offer peptide drug conjugation services to accelerate your peptide drug development. Our scientific team has expertise in peptide conjugation chemistry and is capable of meeting your unique project needs.

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What is Peptide Drug Conjugate?

The principle of peptide-drug conjugate (PDC) is to conjugate cell-targeting peptides with drug molecules to enhance drug targeting and to concentrate the drug in the target tissue, thus reducing its relative concentration in other tissues, increasing effectiveness and reducing adverse effects. The peptides used in PDCs include cell-targeting peptides (CTPs) and cell-penetrating peptides (CPPs). Various linkers have been used in PDCs development to prevent unspecific release of the drug. Payloads available in the PDCs include cytotoxic drugs and radionucleotides. PDC integrates the advantages of peptides with low molecular weight and biodegradability, while not causing immunogenic reactions.

Peptide-drug conjugate Fig 1. Peptide-drug conjugate (Cooper, 2021)

Peptide-drug conjugates (PDCs) consist of three main components, including peptide, linker, and payload.The roles and mechanisms of action of each component are important considerations during the assembly of PDCs.

Toxin drugs are integral to tumor-killing. Highly toxic drug with IC50 values in the subnanomolar range, such as maytansine, camptothecin derivatives, auristatin, Gemcitabine, paclitaxel, Zoloft Melphalan, radionuclides (177Lu-dotatate), or doxorubicin, are recommended in the PDC conjugates. The conjugated cytotoxins meet the followingfour conditions: a clear mechanism of action, small molecular weight, high cytotoxicity, and retained anti-tumor activity after chemical coupling to the peptide.

Peptides selected for PDCs should have the ability to specifically target protein receptors overexpressed in tumor tissue and have strong binding affinity for the target site within nanomolar amounts. Most of the peptides reported so far are linear peptides showing good binding. In addition, the binding affinity of peptides can be increased by stabilizing secondary structures such as α-helix and β-sheet.

RGD (arginine-glycine-aspartic acid)Integrins (α5β1, α8β1 and αIIbβ3)
GnRH (gonadotropin-releasing hormone)GnRH-R (receptor version of the hormone)
SST (somatostatin)SSTR1-5 (somatostatin receptor)
EGF (epidermal growth factor)EGFR: HER1, HER2, HER3, HER4
Angiopep-2LRP-1 (low-density lipoprotein receptor-related protein-1)

Table 1. Examples of peptides used in PDCs

The common functional groups found in the linker region can be broadly divided into four groups: enzyme cleavable (ester, amide, and carbamate), acid cleavable (hydrazone, acetal, ketal, and carbonate), reducible disulfide, and noncleavable (thioether, oxime, triazole, and succinimidyl thioether).

1.Enzyme cleavable linker

(1) Ester and amide

Three molecules of paclitaxel are covalently linked to a single peptide (Angiopep-2) via the side chain of two lysine residues and the N-terminus amine of the peptide, resulting in the formation of the peptide−drug conjugate ANG1005. ANG1005 has showed significant activity against CNS tumors, leading to improved symptoms and an overall increase survival. This effect is particularly notable in LC patients with HER2-positive and HER2-negative breast cancers.

A conjugate of a radionuclide with peptide octreotide, called lutetium 177 DOTA-TATE, was FDA approved in 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEPNETs).

(2) Carbamate

Carbamate linkers employed in the PDCs undergo cleavage within intracellular endosomes or lysosomes under enzymatic conditions. Several somatostatin receptor (SSTR) targeting conjugates using carbamate linker. Among them, the most effective conjugate JF-10-81 showed potent antitumor and antiangiogenic activity.

(3) Dipeptide or Tripeptide

Specific dipeptide or tripeptide sequences can further promote the release of the active drug from the PDCs. PDCs with linkers containing dipeptide (Val-Cit or VC) can be selectively cleaved by enzymes like carboxypeptidase and cathepsin B. The dipeptide is conjugated to Dox via a para-aminobenzyl carbamate (PABC) spacer, which undergoes spontaneous 1,6-elimination subsequent to the enzymatic cleavage of the C-terminal amide of citrulline.

Another peptide sequence utilized for specifically release of drugs at the tumor site is the Ala-Ala-Asn (AAN) tripeptide,  which is cleaved by enzyme legumain.

(4) Amide and a Noncleavable Thioether (Succinimidyl thioether)

(5) Ester and a Noncleavable Triazole

An azide−alkyne cycloaddition to form a triazole has been applied to link peptide with a drug in PDCs due to its ease and efficiency.

2. Acid cleavable linker

(1) Hydrazone

Hydrazone is a common acid-sensitive linker in the design of several drug conjugates. The hydrolysis and stability of hydrazone-forming ketones and hydrazines can vary depending on the original ketones from which the hydrazone is derived. For example, doxorubicin's aliphatic C-13 ketone-derived hydrazone linkers.

3. Reducible disulfide linker

Disulfide linker is used to design PDCs for targeting the EphA2 receptor that is highly expressed in several solid tumors.

4. Noncleavable linker

(1) Oxime

Several PDCs are synthesized by introducing an oxime bond to the C-13 carbonyl group of doxorubicin or daunorubicin. These conjugates are subsequently evaluated for their in vitro and in vivo properties, particularly in the context of targeted therapy for breast, colorectal, and pancreatic cancers.

(2) Triazole

The non-cleavable triazole formed through the alkyne-azide reaction imparts stability to the PDCs structure. Other bonds connecting different regions of the conjugate may facilitate drug release from the PDCs following cellular uptake. An interesting example of a conjugate with a triazole linker is a PDC developed for cancer treatment using photodynamic therapy (PDT).

NameTTPPayloadLinkerIndicationDevelopment phase
ANG1005Angiopep-2PaclitaxelSuccinic acidLeptomeningeal metastases
Glioma Glioblastoma brain tumor, recurrent
Breast cancer brain metastases
Advanced solid tumors with and without bain metastases
Phase III
Phase II Phase II
Phase I
GRN1005Angiopep-2PaclitaxelSuccinic acidBreast cancer brain metastases;
non-small cell lung cancer (nsclc) with brain metastases
Phase II
BT1718MT1-MMP binderDM1DisulfideAdvanced solid tumours
non-small cell lung cancer
non-small cell lung sarcoma
oesophageal cancer
Phase I/II
BT5528EphA2 binderMMAEAmideSolid tumours
EphA2-positive NSCLC
Phase I
BT8009Nectin-4 binderMMAEAmideSolid tumorsPhase I
TH1902TH19P01DocetaxelSuccinic acidSolid tumorsPhase I
TH1904TH19P01DoxorubicinSuccinic acidSolid tumors
G-202 (mipsagargin)DgEgEgEgEThapsigarginAmideSolid tumorsPhase II
NGR015 (NGR-hTNF)CNGRCG(1,5 SS)hTNFAmideMalignant pleural mesotheliomaPhase III
tTF-NGRGNGRAHAtTFAmideMalignant solid tumors lymphomasPhase I
(2,7 SS)
DM-1DisulfideNeuroendocrine tumors arcinoma, small cell lungPhase I/II
CBP-1008CB-20BKMMAEAmideAdvanced solid tumorPhase I
CBP-1018LDC10BMMAEAmideLung tumorPhase I
SOR-C13folateMMAEAmideAdvanced malignant solid neoplasmPhase I
Melflufen (delisted)FlufenamideMelphalanAcOHMultiple myelomaApproved
for marketing
177Lu-dotatate (Lutathera)Tyr-3-octreotate177LuDOTANeuroendocrine tumorsApproved
for marketing
177Lu-PSMA-617Glu-urea-R177LuDOTAProstate cancerPhase I
octreotide18FNOTAPET or GEP-NETs;
Neuroendocrine tumors
Phase I/II/III
[18F]FluciclatideRGD18FPEGPET imagingPhase II
[18F]RGD-K5cyclo(RGDfK)18FNOTAPET imagingPhase II
68Ga-NODAGA-E[cyclo(RGDyK)]2E[cyclo (RGDyK)]268GaNODAGAPET imagingPhase II
68Ga-NOTA-BBN-RGDcyclo(RGDyK) and BBN68GaNOTAPET/CT and PET imagingPhase I
90Y-DOTATOC3Tyr-octreotate90YDOTAPRRTPhase II
99mTc-3PRGD23Tyr-octreotate99mTc3PRGD2Breast cancer SPECT/CT scanPhase I
111In-DTPA-octreotide3Tyr-octreotate111InDTPABrain and central nervous system Tumors PET imagingPhase I

Table 2. Peptide-drug conjugates in clinical trials and approved for marketing. (Fu, Chen; et al.2022)

Although a peptide can provide many properties to PDC, including enhanced tumor penetration, reduced immunogenicity, and cheaper synthesis, the relatively small size of peptide allows for fast renal clearance of PDC. This problem can be addressed by various methods, such as chemical modification (e.g. peptide dendrimers) and physical techniques (e.g. combination of the PDC with nanoparticles).

Our Services for Peptide Drug Conjugates

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Applications of Peptide Drug Conjugate

PDC drugs are mainly used in anti-cancer therapy. Peptide part is used for the targeted delivery of anticancer drug molecules and to reduce systemic toxicity. In some cases, PDC employs cell-penetrating peptides, which can facilitate the proper translocation of anticancer drugs across cell membranes to their desired sites.

In addition to improving pharmacological properties, PDCs can also be used for cancer diagnostics. In this case, the tumor-selective peptides are conjugated to fluorescent dyes, the peptides readily bind to specific receptors on tumor cells, and the fluorescent dyes make imaging of cancer tissue feasible.

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  1. Cooper, B. M., et al. Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs), Chem. Soc. Rev., 2021, 50, 1480-1494.
  2. Alas, M., Saghaeidehkordi, A. and Kaur, K., 2020. Peptide–drug conjugates with different linkers for cancer therapy. Journal of medicinal chemistry, 64(1), pp.216-232.
  3. Fu, Chen, et al. "Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?." Acta Pharmaceutica Sinica B 13.2 (2023): 498-516.
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