HER2 ADC innovation wave!

Author: Duxing

It is reported that at the upcoming ESMO this year, the head-to-head DESTINY-Breast03 research results of DS-8201 and T-DM1 will be unveiled in the form of "LBA, Late-breaking Abstract".

The competition of HER2 ADC drugs in China has become fierce.

(1) T-DM1: The first ADC drug to be marketed in China

Kadcyla (enmetrastuzumab, T-DM1) is a HER2 ADC drug.

In the structural design, T-DM1 uses trastuzumab, the cytotoxic drug uses the tubulin inhibitor DM1, and the linker uses MCC Linker

From the mechanism of action, T-DM1 can bind to the subregion IV of the HER2 receptor on the cell membrane surface.

Figure: T-DM1 mechanism of action

Data source: Roche

Since its launch, with its extensive breast cancer patient population and unique treatment mechanism, T-DM1 global sales have continued to rise.

(2) Vidicituzumab: the first domestic ADC drug to be marketed

Vidicituzumab (RC48) is a HER2 ADC drug independently developed by Rongchang Biologics.

From the structural analysis, the mAb of vedicitumumab adopts Disitamab, with an EC50 value of 6.

Figure: The molecular structure of Vidicuzumab

Data source: Rongchang Biological

The indications of T-DM1 for gastric cancer have been broken, and Vidicuzumab provides a new treatment for patients with advanced gastric cancer

(3) DS-8201: Four surprises with dazzling data

Enhertu (DS-8201) is a masterpiece in the field of HER2 ADC, jointly developed by Daiichi Sankyo and AstraZeneca

The choice of DNA topoisomerase inhibitors takes into account both safety and efficacy

Figure: DS-8201 structure

In 2019, DS-8201 was approved by the FDA as an indication for HER2-positive breast cancer

In 2020, DS-8201 once again won the HER2-positive gastric cancer indication, and the data is extremely eye-catching

(4) ARX788: Site-specific coupling technology of non-natural amino groups

The domestic development and commercialization rights of ARX788 belong to Xinma Bio, a subsidiary of Zhejiang Pharmaceuticals, which is quoted from AMBRX, a leading ADC drug company in the United States

The core technology of ARX788 is the site-specific coupling technology of unnatural amino acids, which can generate ADC drugs with a DAR of 2 to improve the uniformity of the drugs

The Ambrx unnatural amino acid technical route is divided into three steps: the first step is to synthesize natural amino acids in vitro that meet the requirements of the preparation of medicines; the second step is under the action of synthetase, the natural amino acids are connected with special tRNAs and transported to the ribosome, and the third step tRNA recognizes special codons and precisely inserts natural amino acids into specific parts of the polypeptide chain

Figure: Schematic diagram of unnatural amino acid site-directed coupling technology

(5) A166: Lysine site-specific coupling technology

A166, developed by Kelun Pharmaceutical Holdings subsidiary Kelun Botai, is the third generation of antibody conjugate drugs targeting HER2.
The new toxin molecule (Duo-5, tubulin inhibitor) can be site-specifically coupled by protease cleavable Linker.
Linked to HER2 antibody (trastuzumab)
.

At ASCO in 2021, Kelun Pharmaceutical announced the results of the Phase I clinical study of A166.
At effective doses of 4.
8 and 6.
0 mg/kg, the ORRs of 36 patients with evaluable HER2-positive breast cancer were 59.
1% (13/22).
) And 71.
4 (10/14); 4 cases of breast cancer patients with low HER2 expression that can be evaluated for curative effect resulted in 1 case of PR, 2 cases of SD and 1 case of PD
.
The median PFS was not reached, and one patient in the 4.
8 mg/kg dose group had received A166 treatment for more than 19 months
.
In terms of safety, A166 is generally well controllable, but there are adverse ocular events
.
For ocular toxicity, it can be recovered after symptomatic treatment
.

(6) Summary

Affected by the global innovation wave and the update and iteration of ADC drugs, HER2 ADC has become one of the most competitive areas in the domestic ADC field.
Rongchang Biological, Zhejiang Pharmaceutical, Kelun Pharmaceutical, Jiahe Biological, Fosun Pharmaceutical, etc.
are all located here
.
In addition to HER2 ADC, BeiGene's ZW49 is a HER2×HER2 ADC that can simultaneously bind two non-overlapping epitopes of HER2, which is expected to improve the targeting of drugs
.
However, the research and development of HER2 ADC drugs has not been smooth sailing.
Biotech’s BAT8001 has broken down.
In the future, companies related to HER2 ADC will need to race against time on the one hand and accelerate R&D to market first; on the other hand, they will adopt a differentiated path and multi-indication layout.
, It has made many breakthroughs in breast cancer, gastric cancer, urothelial cancer and other indications
.