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The pace of cancer treatment has not stopped
.
Small molecule targeted drugs to monoclonal antibodies, to "1+1>2" bispecific antibodies and ADCs, and then to the newly excited bispecific antibodies ADC drugs, while confirming the pre-historical trend, but also illustrating the continuous shortcomings and defects
of drugs.
The continuous iteration of tumor treatment has brought good news to the public, and new challenges and confusion are rapidly gathering
for the industry and pharmaceutical companies.
On the eve of the wind, there are good and bad times
On the eve of the wind, there are good and bad timesWhen the storm comes, the vanguard collapses
.
At the 2022 ESMO conference, Zymeworks, a listed company on the US stock market, released its HER2 bispecific antibody ADC product - ZW49, which failed to meet expectations in phase I clinical data for the treatment of solid tumors, causing the stock price to plummet.
This undoubtedly puts pressure
on companies developing bispecific antibody ADC drugs.
Although Pioneer is cold, different from the previous generation of tumor treatment methods, the advantages of bispecific antibody ADC drugs are still promising
.
Dual antibody ADC drugs, which combine the advantages of bispecific antibodies and ADCs, are a more novel concept
.
Compared with monoclonal antibodies, on the one hand, bispecific antibodies target tumor cells more specifically to increase drug safety; On the other hand, the synergistic endocytosis of the two targets is promoted through cross-linking, which not only improves the efficiency of toxins entering tumor cells, but also further inhibits tumor cell growth signals by reducing the expression of receptor proteins on the cell membrane, so as to achieve better therapeutic effects
.
Mechanism of action of bispecific antibody ADCs and their advantages Source: Bioset
In this way, the bispecific antibody ADC with multiple advantages will become a new track
for many pharmaceutical companies to compete for the flow in the future.
However, because the research in this direction is still in the development stage, there are not many
preclinical products under research.
There are roughly two reasons:
First, there are few antibody skeleton molecules that can be used for the construction of bispecific antibodies, and the targets are very concentrated, only there are good optional antibody molecules on several targets such as HER2, HER3, EGFR, MUC1, etc.
, and there is a lack of sufficient "skeleton" to quickly build a stable expression of bispecific antibody ADC molecules;
Second, most of the antibodies against these molecules are obtained through blocking activity screening, and whether their endocytic activity meets the needs and whether it can be used as the best candidate antibody molecule for ADC drugs is not yet known
.
Test the water and blossom more
Test the water and blossom moreAt present, pharmaceutical companies at home and abroad are conducting clinical or preclinical research
on bispecific antibody ADCs.
Zymeworks：ZW-49
The ZW-49 is Zymeworks utilizing its proprietary Azymetric™ Bispecifics and ZymeLink™
The ADCs platform jointly developed the resulting bispecific antibody ADC drugs
.
Ability to specifically bind to two non-overlapping epitopes of HER2 receptors simultaneously, the pertuzumab binding site and trastuzumab binding site
.
In order to achieve a good therapeutic effect in clinical application, it will have a good therapeutic effect
on patients resistant to new ADC drugs such as trastuzumab, pertuzumab, and even TDM-1.
Given the great potential of the ZW-49, in 2018, BeiGene partnered with Zymeworks
Inc.
entered into a strategic collaboration
for the clinical development and commercialization of ZW49 and ZW25.
The antibody part of ZW49 adopts an antibody structure similar to ZW25 (bispecific antibody, binding two non-overlapping epitopes of HER2 at the same time), through Zymelink technology, the connected Payload is a microtubule inhibitor derived from the chemotherapy drug auristatin, which can theoretically achieve a HER2 binding effect similar to ZW25 in the patient's body, thereby releasing cytotoxic substances carried inside cancer cells and playing a maximum killing effect
.
In mouse tumor models, ZW49 exhibits stronger antitumor activity
than T-DM1 and DS-8201.
In January 2021, Zymeworks announced some data
from the Phase I clinical trial of ZW-49.
Results showed that ZW-49 showed antitumor activity
at all treatment regimens and dose levels.
Partial environmental (PR) and disease stabilization (SD)
were observed in both Q2W and Q3W dosing regimens.
In all 35 patients treated with ZW-49, there were no treatment-related hematotoxicity, pulmonary toxicity, or hepatotoxicity
.
More than 90% of adverse reactions were mild or moderate.
AstraZeneca: MEDI4276
It is a biepitope tetravalent HER2 ADC drug
.
MEDI4276, epitope similar to pertuzul, fully human antibody, recognizes domain
2) is the skeleton, connected to the scFv structure
of trastuzumab (recognition domain 4).
The recognition epitopes of 39S and trastuzumab are located at opposite ends of HER2 ECD, > 90 away from each other
Å
。 DAR is 4 and linker is maleimidocaproyl
Linker, the toxin is tubulysinwarhead
.
However, the clinical development of MEDI4276 was so frustrated that its development
was terminated.
MEDI4276 has indeed achieved some efficacy
in patients who are resistant to trastuzumab, pertuzumab and TDM1 therapy.
However, toxicity problems caused the death of the entire project
.
In the entire ADC field, the main cause of toxicity problems actually comes from linker/payload, while MEDI4276 has a certain degree of targeted toxicity, causing DLT
.
Therefore, while solving the problem of non-response of drugs with low expression of antigens, the toxicity of dual-epitope ADCs is worth thinking about and is also a very big hidden danger
.
The choice of the toxicity of the toxin, and even the choice of DAR, must be considered, rather than simply rough
.
ZW49 has made certain improvements, at present, only showing preliminary clinical efficacy, not amazing, but there has not been a serious toxicity problem related to MEDI4276, can still continue to climb, its follow-up results are still worth looking forward to
.
Baileys Pharmaceutical: BL-B01D1
BL-B01D1 is a bispecific antibody ADC
targeting EGFR/HER3 developed by Baileys Pharmaceutical.
In addition to bispecific ADCs, Baili Pharmaceutical has also deployed bispecific antibodies
to EGFR/HER3.
From its published patent, the structure of EGFR/Her3 bispecific antibody may be shown in the figure below, which is the 2+2 symmetric structure of fused scFv on a complete antibody (subject to the company's disclosure).
In terms of mechanism of action, BL-B01D1 can not only block the relevant binding of EGFR and HER3 with ligands at the same time, but also enter the cell through endocytosis after binding with EGFR and HER3, and release the small molecule toxin ED04 by hydrolase enzyme digestion, which prevents DNA replication and RNA synthesis of tumor cells, and destroys the DNA structure, thereby further killing tumor cells
.
At present, the drug has entered the clinical trial
in China.
Jerry Corning: JSKN003
JSKN003 is a bispecific antibody ADC
targeting HER2 developed by Alpha Corning.
This bispecific antibody is modified and designed based on KN026, which, similar to ZW-49, are two different epitopes (ECD4/trastuzumab and ECD2/pertuzumab)
targeting HER.
JSKN003 utilizes site-specific coupling with DAR values of 3-4, both in animal models with low HER2 expression and N87 with high HER2 expression
In the CDX model, its efficacy and efficacy and the first three kyos' ENHERTU (DS-8201a
Quite
.
In addition, in terms of stability, JSKN003 has shown good stability in serum, so it may theoretically have a better safety profile
.
In addition to the development of bispecific antibody ADC drugs, Corning Jereh is currently also deploying bispecific antibody conjugate modulator-related drugs
.
Regenron：REGN5093- M114
REGN5093-M114 is a bispecific antibody ADC
developed by Regenron that targets two different epitopes of MET.
The antibody is a 1+1 asymmetric bispecific antibody that passes through M114
The linker links the antibody to the toxin M24 (a maytansin derivative) with a DAR value of around
3.
2.
It can bind different epitopes of two MET at the same time, and can effectively block the binding of HGF and MET, thereby preventing the activation of related pathways; In addition, after the antibody binds to the MET on the surface of tumor cells, the 2+2 type complex formed by the antibody and MET can be internalized, entered the tumor cell and degraded in lysosomes, thereby reducing the expression of MET on the cell surface
through recirculation.
In addition, the enzymatically cleaved linker in REGN5093-M114 releases M24 toxin and inhibits tumor growth
by acting on tubulin.
Unlike other antibodies, REGN5093-M114 naked anti-resistance itself also has a certain effect of inhibiting tumors, and has shown good efficacy
in a variety of preclinical models.
At present, Regeneron has promoted both the naked anti-REGN5093 and ADC bispecific antibody REGN5093-M114 to the clinic
.
Sutro + Merck: M1231
M1231 is a targeted MUCI/EGFR bispecific antibody ADC
developed by Sutro and Merck.
The bispecific antibody ADC uses Sutro's unnatural amino acid fixed-point coupling technology and prevents mismatch
of the two heavy chains through Merck's SEED bispecific antibody technology platform.
Among them, the antibody targeting MUCI is scFv, while the antibody targeting EGFR is in the form of Fab, and the design does not have the problem
of light chain mismatch in traditional bispecific antibodies.
In production, the expression of the antibody is using Sutro's cell-free system XpressCF, and unnatural amino acids are inserted at a fixed point during the production process to facilitate the subsequent targeted conjugation
of bispecific antibodies.
The toxin side uses the microtubule inhibitor hemiasterlin and conjugates antibodies to the toxin via a cleavable Val-Cit linker
.
Merck chose MUCI/EGFR as a target because relevant studies have shown that MUCI/EGFR is co-expressed in a variety of tumor cells, such as ESCC, NSCLC, SCCHN, etc.
, and its co-expression is very low in normal tissues, so it can theoretically reduce On-target toxicity and improve the medication window
.
In addition, his studies have shown that antibodies bind to two antigens on the tumor surface at the same time, making the antibody rapidly endocytosis and releasing the responding toxin to inhibit the growth
of tumor cells.
In preclinical PDX animal models, a single dose of 8mg/kg mice can inhibit tumor growth and even clear tumors
to a certain extent.
At present, the drug has entered the clinic
.
Biosetu: YH012
Biosetto's bispecific ADCs are built on its RenLiteTM bispecific antibody platform,
RenLiteTM uses the common light chain method to prevent the mismatch of bispecific antibody light chains, and at the same time uses Knob-In-Hole to prevent the mismatch of antibody heavy chains, and the platform can realize the production
of high-purity bispecific antibodies.
On this basis, it uses interstreptocysteine for coupling, linker is cleavable dipeptide VC (valine-citrulline), and toxin is MMAE
.
In NCI-N87 tumor cells, the bispecific antibody ADC YH012 targeting Her2/TROP2 can be rapidly internalized by tumor cells, and its internalization efficiency is due to single-target control ADC drugs
.
In vivo models, the bispecific antibody ADC YH012 can effectively inhibit the growth of tumor cells, and is superior to monoclonal antibodies conjugated to the same toxin in efficacy, and better than higher doses of bispecific naked antibodies
.
Conclusion
ConclusionAt present, the ADC track is becoming more and more crowded, but bispecific antibody ADCs combine the characteristics and complexity of bispecific antibodies and ADCs, and need to fully understand the mechanism and principle of action, so they have a broader competitive advantage
.
At present, bispecific antibody ADCs are still in their infancy, and further clinical verification
is needed for their safety and efficacy.
Compared with developed regions such as Europe, the United States and Japan, domestic enterprises should take differentiation as the core, start from originality, and embrace new directions, which is the general trend
.
The first breakthrough is
to understand the endocytosis and mechanism of ADC - the extremely important first step in the efficacy of ADC in vivo.
In addition, if you think conservatively alone, it is undoubtedly a mistake
to think that you can make a better ADC in a low-risk situation.
We must really calm down, start from the mechanism, study hard, and break from the inside in order to give birth to a new life
.
Resources:
Resources:
1.
Progress and hidden dangers of bispecific antibody ADC drugs! Medicine Times, 2022-03-01.
Progress and hidden dangers of bispecific antibody ADC drugs! Medicine Times, 2022-03-01.
2.
"A New Generation of Therapeutic Antibodies-Dual Antibody ADC Drugs", Biosetu, 2022-03-09.
"A New Generation of Therapeutic Antibodies-Dual Antibody ADC Drugs", Biosetu, 2022-03-09.
3.
The Next Stop of Dual Antibodies: Dual Antibodies ADC? Antibody Circle,2022-07-27.
The Next Stop of Dual Antibodies: Dual Antibodies ADC? Antibody Circle,2022-07-27.
4.
"A track better than double antibodies and ADCs?" Overseas pioneers were frustrated, and several domestic pharmaceutical companies laughed", Gazelle She, 2022-09-26.
"A track better than double antibodies and ADCs?" Overseas pioneers were frustrated, and several domestic pharmaceutical companies laughed", Gazelle She, 2022-09-26.
