ADC: A "biological missile" for cancer treatment?

Is ADC the perfect choice?

GL Ventures

Antibody-conjugated drugs are like precision guided missiles with nuclear warheads, powerful and precise
.
An ideal ADC can accurately identify tumor cells without disturbing normal cells; after entering the cell, it releases enough cytotoxic drugs to kill tumor cells
.
Therefore, under ideal conditions, we can use larger doses of drugs to attack tumors in patients without causing adverse reactions caused by systemic chemotherapy drugs
.
At the same time, this method of directly "poisoning" dead cells is also more powerful than targeted therapy and immunotherapy
.
But all these happy endings are based on "ideal"
.
In the process of developing and applying ADCs, scientists are faced with many challenges
.
The earliest marketed Mylotarg caused fatal hepatotoxicity because its unstable linker decomposed before recognizing tumor cells and released cytotoxic drugs, which in turn damaged normal liver cells and caused liver failure
.
These drugs did not point to the "tumor cells" as we imagined, but accidentally injured the surrounding people eating melons, so we call it the "off-target effect"
.
In treatment strategies including targeted therapy and ADC, off-target effects are the biggest challenges
.
Even if the connecting object keeps the explosives tightly tied to the navigation system, problems with our navigation system can cause off-target effects
.
If the selected target is not expressed enough on the tumor cells, or the tumor cells cannot be distinguished from normal cells, the antibody will not be able to accurately identify the cancer cells.
This powerful express will be sent to the innocent king's house next door
.
It is precisely because of the off-target effect that there are strict limits on the dose of ADC
.
Too small a dose cannot kill enough tumor cells, and the toxic side effects caused by a large dose can threaten the lives of patients
.
Mylotarg was reborn after repeated adjustments to the dosage and regimen
.
There are currently more than fifty clinical trials on ADCs worldwide, but there are only a handful of drugs on the market
.

Similar to monoclonal antibody drugs, the current indications of ADC are mostly concentrated in malignant tumors of the hematopoietic system
.
Most clinical trials and approved drugs target lymphoma and leukemia, and among solid tumors, only breast cancer has drugs on the market
.
This is related to the complex tumor microenvironment of solid tumors and the diversity of cell surface targets
.
We look forward to the launch of more ADC drugs for solid tumors in the future, benefiting more cancer patients
.
(The content is reviewed by "Xiehe Eight" of Peking Union Medical College)

references:

[1]Dan N, Setua S, Kashyap VK, Khan S, Jaggi M, Yallapu MM, Chauhan SC.
Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications.
Pharmaceuticals.
2018; 11(2):32.
https://doi.
org/10.
3390/ph11020032

[2]Nejadmoghaddam, Mohammad-Reza et al.
“Antibody-Drug Conjugates: Possibilities and Challenges.
” Avicenna journal of medical biotechnologyvol.
11,1 (2019): 3-23.