Preliminary exploration of new drug conjugates: PDC and ISAC have different situations

The therapeutic principles of ADC drugs have been relatively clear
.

Since the first ADC was approved for marketing, after nearly 20 years of development, ADC has been updated, and the third-generation ADC drugs developed so far have brought this field into an explosive period.

The extension of ADC concept

The extension of ADC concept

In order to reduce the damage of chemotherapy drugs to healthy cells, so that cytotoxic drugs can be accurately delivered to the lesion site, 100 years ago, Paul Ehrlich, the father of chemotherapy, proposed the concept of "magic bullet" using antibodies to target cancer treatment, and then there was Early ADC development
.

Over the past ten years, after continuous iterative optimization, the therapeutic value of ADC has been verified and recognized
.

ADC itself as a successful example of drug conjugation mode has also fully driven the exploration and development of new drug conjugation modes

PDC: To be the successor of ADC

PDC: To be the successor of ADC

Although the overall performance is not better than ADC
.

However, with the development of the new drug conjugate concept, the R&D trend of PDC drugs, which is the successor of the next generation ADC, has gradually emerged, which has attracted the industry's optimism

Among the new drug conjugation combinations, PDC drugs have taken the lead in the development progress due to their significant advantages such as stronger tumor penetration, lower immunogenicity and lower production costs, and more than ten companies have been deployed.

.

Currently a leading and active overseas company in the PDC project
.

There are two approved for listing globally

IS A C: Preliminary Probe for a Lost Opening

IS A C: Preliminary Exploration of the Opening Loss IS A C: Preliminary Exploration

Compared with the smooth development of the PDC as a whole, the immune-stimulating ADC has a bad start
.

The idea of ​​ISAC is to couple immune agonists to tumor-targeted antibodies, and to use antibodies to deliver immune agonists to the tumor microenvironment and release them locally, so as to solve the obstacles of systemic administration of immune stimulants and improve anti-tumor treatment at the same time.

The potential application prospects of ISAC also attract Novartis, Takeda and several domestic companies such as Cinda, Hengrui, Baekje, and Kai Tak
.

Innovent chose to bring in from pioneering company Bolt to co-develop ISAC drug candidates for the treatment of tumors

In terms of overall development progress
.

The development of ISAC is at an earlier stage than PDC

On September 13, 2021, the pioneering company Silverback Therapeutics announced the interim Phase I/Ib clinical data of its new immune-agonist ADC drug SBT6050 at the ESMO meeting.
Among 14 evaluable patients, its overall response rate ORR was only 7%
.

After the news was announced, Silverback’s stock price plummeted 25% that day, and the decline was difficult to close.

Subsequently (December 6), Bolt Therapeutics also reported dismal Phase I/II clinical data of ISAC drug BDC-1001, with an overall response rate ORR of only 2.
5% among 40 evaluable patients
.
This result was difficult to satisfy investors.
After the results were announced, Bolt Therapeutics shares were halved, plummeting 55.
8%
.

The silverback and Bolt pioneers' first-game losses also made ISAC's prospects cloudy for a while
.

Xiaobian summary

Xiaobian summary

Standing on the shoulders of ADC, the development and application scenarios of new conjugated drugs have a broader imagination
.
Although the therapeutic concept of grafted ADC is simple, the combination of load, linker and targeted functional molecule is not a simple permutation and combination problem
.
The development of conjugated drugs faces more complex pharmacological and toxicological problems
.
In order to differentiate on the ADC, the development of a new generation of ADC drugs requires more proof-of-concept and clinical validation, and there is a long way to go to explore
.

Reference source: 1.
https://doi.
org/10.
1038/s43018-020-00136-x

Reference source: 1.
https://doi.
org/10.
1038/s43018-020-00136-x