PDC: The next glorious destination for conjugated drugs?

Author | Leaf

Catalyzed by technological progress and commercial value, the types and concepts of conjugated drugs are constantly expanding.

Among the conjugated drugs other than ADC, it is not clear who will become the next "honor", but PDC may have a higher probability due to the relatively large number of products on the market and in the clinical development stage

Definition of PDC

PDC, Peptide Drug Conjugate, as its name implies, is a type of drug coupling form that uses peptide molecules as a target

References [1]

The biggest advantage of RDC is that it does not require the target to be endocytosed, as long as it can be localized to tumor cells, imaging or radiotherapy can be achieved

Note: Pepaxto is not included; unpublished structures of radiotherapy are not included

On the whole, the structural composition of various conceptually coupled drugs is the same, usually consisting of three parts

Reference 2

1.

Among PDC drugs, the main function of polypeptides is also to achieve targeted positioning

What is important is that the greater advantages of peptides over antibodies are production costs and technology accumulation

2.

The Linker of the PDC drug is not fundamentally different from the ADC

Reference 2

3.

PDC drug load also involves many types

PDC representative drugs

Several conjugate drugs that carry radionuclides developed by Novartis are also representative of PDC drugs

1.

SORT1, also known as neurotensin receptor 3, is a membrane-bound receptor that belongs to the VPS10P receptor family

Thera technologies developed the PDC drug TH1902 for the SORT1 receptor

The peptide molecule in TH1902 can target the SORT1 protein expressed in a variety of cancers, and the cleavable Linker links the peptide with the toxic load docetaxel
.

In terms of the mechanism of action, TH1902 applies the "lock-and-key theory" to conjugated drugs to competitively bind to the target SORT1
.

Another similarity between PDC drugs and ADC drugs is that they achieve precise release of payloads and reduce exposure to normal tissues to improve tolerance and efficacy
.
In a sense, conjugated drugs are also like a kind of drug delivery technology
.
The pre-clinical research data of TH1902 indeed illustrates this nature
.

Judging from the results, TH1902 uses Linker (succinic acid) to form docetaxel and peptide molecules in a ratio of 2:1, enters the cell through a sortin-dependent mechanism, and can effectively bypass the P-pg efflux pump.
(MDR1) function to increase intracellular concentration and achieve better tumor migration and growth inhibition
.

For TH1902, the value of peptide molecules is like the albumin in paclitaxel, which can be said to open up a new type of delivery technology
.
By reducing the accumulation in normal tissues, while reducing side effects, it not only improves drug tolerance, but also expands the therapeutic window of drugs
.
Compared with albumin, peptide molecules have a stable source and cost advantage.
If TH1902 shows the potential similar to clinical data, it is not impossible to extend the application to paclitaxel
.

2.
CBX-12

Unlike most conjugated drugs that achieve intracellular aggregation of payloads through a clear target endocytosis or transport, Cybrexa therapeutic's PDC drugs based on alphalex are a type of antigen-independent intracellular drug delivery technology
.
Specifically, the pH-dependent insertion peptide (pHLIP) is used to target acidic tissues
.

In a normal tissue environment, the pH insert peptide does not perform the insertion function of the cell membrane, and cytotoxic drugs cannot penetrate the cell membrane into normal cells; in the acidic tumor environment, the pH insert peptide performs the insertion function through the physical mechanism of membrane-related folding , Cytotoxic molecules are released in the cell by lysis
.

CBX-12 carrying Enhertu toxin topoisomerase I inhibitor (Exatecan, DX-8951) is the only drug in Cybrexa's research product that has entered clinical research
.
In addition to CBX-12, Cybrexa is also developing products based on different toxins (DM4, MMAE, DDR inhibitors) based on alphalex
.

In fact, Cybrexa's alphalex polypeptide technology has also been reported in the literature [3]
.
The pHLIP family peptides have the same characteristics in their main sequences and show the same mechanism of action
.
These common features mainly include: the N-terminal region (sequence 1) contains 3-20 residues, mainly composed of polar amino acids that increase the overall solubility of the peptide; the middle region (transmembrane sequence) contains 15-25 residues, It is mainly composed of hydrophobic residues, but also includes amino acids that are negatively charged at physiological pH but neutrally charged due to protonation at low pH; and a C-terminal region containing 0-10 residues (sequence 2)
.
The pHLIP family of peptides may contain some additional protonable residues or functional groups, which is convenient for Linker to link peptides and loads
.

Reference 3

It can be seen from the structure of CBX-12 that CBX-12 adopts the same amino acid sequence as Var 3 (Var 3)
.
In the in vitro stability test results of mouse, rat, dog and human plasma, CBX-12 showed good stability.
No toxin release was detected within 8 hours, and very little toxin release at 24 hours was fully verified.
CBX-12 is stable in blood circulation
.
Moreover, in the xenotransplantation animal model, the blood circulation stability and tumor cell selectivity of CBX-12 were once again confirmed
.

Most importantly, compared to Exatecan (DX-8951, Ixinotecan) alone, peptide-bound CBX-12 shows a more powerful tumor suppressor effect in a variety of tumor models
.
In the treatment with unconjugated Exatecan, the model animals consistently showed significant weight loss or fluctuations, while CBX-12 had a smaller effect on body weight, which also showed the tolerability advantage of CBX-12
.
In addition, unconjugated Isartecan also caused damage to the entire organs of the animal, including the significant GI toxicity observed under the microscope
.
In contrast, animals taking CBX-12 showed no detectable gastrointestinal toxicity
.

Reference 4

Cybrexa even emphasized that CBX-12 has the potential to surpass the ADC drug Enhertu (DS-8201) in some tumor types
.
Relatively speaking, in the JIMT-1 model (breast cancer) reported in different literatures [5], the preclinical data of CBX-12 showed a higher trend of tumor suppression
.
Of course, this comparison is not rigorous and cannot be used as evidence that CBX-12 is superior to Enhertu.
It still needs further clinical verification
.

References 4, 5

Summarize

In addition to the ADC drug boom, more conjugated drugs have yet to show real clinical breakthroughs
.
Compared with other conjugate drugs, several peptide nuclide conjugate drugs have been marketed in the field of PDC, which is considered to be a good performance
.
Possibly, PDC drugs will develop more rapidly only after more representative drugs have self-certified value
.
After all, compared with other conjugated drugs, the technological and production advantages of peptide drugs are destined to have a broader industrial foundation for PDC drugs
.

However, PDC drugs also have challenges and thresholds, such as the screening of target peptides
.
However, PDC drugs that are different from traditional ADCs have begun to emerge, giving them distinct potentials, such as CBX-12
.
Of course, the value of drugs is clinical benefit, and whether PDC drugs can become the glory after ADC requires clinical verification
.

references

1.
Bethany M Cooper, et al.
Peptides as a platform for targeted therapeutics for cancer: peptide–drug conjugates (PDCs).
Chem Soc Rev, 2021, 50, 1480-1494

2.
Hoppenz P, et al.
Peptide-Drug Conjugates and Their Targets in Advanced Cancer.
Therapies Front Chem, 2020, 8:571.

3.
Linden C Wyatt, et al.
Applications of pHLIP Technology for Cancer Imaging and Therapy.
Trends Biotechnol.
2017, 35(7): 653–664

4.
Sophia Gayle, et al.
Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity.
NAR Cancer, 2021, 3(2): 1-13

5.
Yusuke Ogitani, et al.
DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.
Clin Cancer Res, 22(20): 5097–108