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Will the “marriage of the century” between Oncolytic bacteria and ADCs spark passion in the field of tumour immunotherapy?

ADC drugs have been one of the rising stars in the fight against cancer in the last decade.ADC's new oncology treatment: a "supernova" in the anti-tumour field

The fight against disease is a constant "survival challenge" for mankind. For example, when it comes to cancer, as deadly as it sounds, we are determined to eradicate it against all odds.

In the last hundred years, the global fight against cancer has been fruitful, although mankind has not yet completely conquered cancer, and after all, the "community" of cancer, which is made up of various malignant tumours, is also a complex system with deep roots.

From the classic "triad" of surgery, radiotherapy and chemotherapy to immunotherapy, which has re-emerged as the fourth pillar of cancer treatment, the world has seen a new era of blossoming in the field of anti-tumour treatment, with more and more emerging treatment paradigms. The emergence of more and more new cancer treatment paradigms has also given hope to countless cancer patients and given them the courage to face life positively.

ADC drugs have been one of the rising stars in the fight against cancer in the last decade.

ADC's new oncology treatment: a "supernova" in the anti-tumour field

ADCs are a class of drugs in which a biologically active cytotoxic drug is attached to a monoclonal antibody through a chemical bond, and the monoclonal antibody acts as a carrier for the targeted transport of the cytotoxic drug into the target cell for action, also known as an antibody-drug conjugate (ADC).

Research on ADC dates back to the 1980s, but the first ADC drug product (Mylotarg, developed by Pfizer to treat acute granulocytic leukaemia) was not approved for marketing until 2000. However, it was withdrawn in 2010 due to limitations in coupling technology, targeting and efficacy, and the instability of the complete antibody-coupled drug in the bloodstream, leading to lethal toxicity. This has cast a further shadow over the already uncertain ADC drug research.

In 2011, Takeda's Adcetris, jointly developed with Seattle Genetics, was approved by the FDA to treat Hodgkin's lymphoma and systemic mesenchymal large cell lymphoma. 2013 saw another breakthrough in ADC research when the FDA approved Roche's Kadcyla for the treatment of HER2-positive breast cancer, the first of its kind to target solid tumours antibody-coupled drug. With the development of these two successful drugs, ADC drugs are once again entering the research landscape with a blaze of enthusiasm.

Mechanistically, ADCs are complex molecules made up of antibodies coupled to biologically active cytotoxic drugs. By combining the specific targeting ability of antibodies with cytotoxic drugs, ADCs can sensitively differentiate between healthy and diseased tissues.

As a novel approach to oncology, ADC works by selectively delivering potent chemotherapeutic cytotoxins directly to tumour cells, aiming to maximise therapeutic activity against tumour cells while minimising toxicity to healthy cells.

Structurally, ADCs generally consist of three components:

  • a monoclonal antibody that selectively targets a unique antigen preferentially expressed on tumour cells or other cells in the tumour microenvironment
  • a cytotoxic chemotherapeutic payload that kills the target cells, usually consisting of microtubule inhibitors such as MMAE or DM1 or DNA damaging agents
  • a linker that connects the two, designed to stabilise circulation and enable release of the payload within the target cell

Statistics show that the FDA has approved 12 ADC drugs for marketing in the US, while the domestic NMPA has approved 3 ADC products for marketing in China. The following chart shows the ADC drugs that are currently marketed in China and the US.

ADC: combines the key benefits of antibody therapy, chemotherapy and small-molecule inhibitor therapy

Traditional oncology therapies, such as antibody drugs and chemotherapy, have their limitations. For example, the safety and efficacy profile of antibody drugs can be affected by issues such as batch differences, background signal interference and side effects; on the other hand, conventional chemotherapy shows high off-target toxicity and can lead to an increased risk of infection, hair loss and nausea due to the inability to distinguish healthy cells from tumour cells.

In contrast, ADC has unique targeting capabilities and better clinical trial results, making it a promising treatment option for cancer patients.

It can be said that ADC combines the key advantages of antibody therapy, chemotherapy and small-molecule inhibitor therapy and that the main advantages of ADC over the traditional oncology paradigm are as follows.

01 the antibody portion of ADC can target cancer cells directly and precisely, providing greater precision and selectivity than conventional chemotherapy, offering higher efficacy.

02 the therapeutic window and efficacy are enhanced: the chemical payload component of ADC provides enough cytotoxic agents to destroy cancer cells. Because ADCs can target cancer cells more precisely and selectively, ADC drugs can be given to patients at higher doses that would not be tolerated by conventional chemotherapy at the same dose. Such cytotoxic sufficiency further enhances the efficacy of ADC against tumour cells.

03 resistance reduction: optimised monoclonal antibodies in combination with payload ADCs can help reduce or possibly even resolve targeted drug (e.g. EGFR-TKI) resistance or their resistance by modifying some ADC components, including changing the cytotoxic payload of the ADC to a toxin with unfavourable efflux substrate, modifying the linker to improve hydrophilicity and modifying the linker-cytotoxic structure. ) resistance or their resistance problems.

04 the synergistic effect: ADC benefits from the powerful cytotoxicity of small molecule drugs and the high targeting capacity of monoclonal antibodies. After administration of the ADC drug, the antibody partially binds specifically to the target cell; the ADC is phagocytosed by the tumour cell and enters the lysosome for degradation, while the small molecule cytotoxic drug is released into the cell in sufficient quantity, thus killing the tumour cell.

05 A large potential patient population. By exploring more cancer-specific antibodies and novel chemistries with greater cytotoxicity, novel ADCs can be developed and applied to different types of cancer and to patients who have responded poorly to current therapies. In the future, more cancer indications may be included in the ADC portfolio.

ADC Drugs Market Size Overview

In terms of market size, the current global ADC drug market is growing strongly, and the global and Chinese ADC drug markets are expected to maintain high growth rates shortly.

According to statistics, the worldwide market for ADC pharmaceuticals will be worth US$2.8 billion in 2019 and will increase at a CAGR of 30.6 percent from 2019 to 2024 and 12.0 percent from 2024 to 2030, reaching US$10.4 billion and US$20.7 billion in 2024 and 2030, respectively.

The Chinese market for ADCs will not emerge until 2020, when it is predicted to reach RMB7.4 billion in 2024 and RMB29.2 billion in 2030, rising at a CAGR of 25.8% from 2024 to 2030.

In addition to the general drivers of the oncology drugs market, the domestic ADC therapy market is driven by

First, the growing ADC drug pipeline.

The ADC drug pipeline continues to grow due to the superior efficacy of the ADC products already on the market. The FDA has approved 12 ADC drugs in the US, while the State Drug Administration has approved three ADC drugs in China.

In addition, over 20 ADCs are currently in clinical development in China, seven of which are in or have passed the Phase III clinical stage. the widespread use of ADC drugs across different cancer types, coupled with rising patient affordability and public health awareness, will sustain further growth in the ADC market.

Secondly, there have been continuous advances in relevant technologies.

ADC drug development involves several key technical challenges, including the stability of the linker in the circulation, the nature and delivery mechanism of the linker, binding to antigens, payload release and potency, and the binding site.

Significant efforts have improved all components to enhance ADC targeting, safety and efficacy in solid and haematological cancers.

The development of advanced novel ADC drugs has seen breakthroughs in technological advancements, with increased therapeutic windows, improved stability, improved pharmacokinetics, slower dissociation, increased efficacy, higher DAR values and overall improved hydrophilicity compared to previous generations of ADC drugs. This continued technological advancement will further drive the growth of the ADC therapeutic market.

Thirdly, there is a wide range of therapeutic areas.

The currently available therapeutic areas and indications for ADCs include a wide range of solid tumours and haematological cancers. At the same time, ADC drugs may have applications in other therapeutic areas, such as the treatment of infectious diseases, autoimmune diseases and cardiovascular diseases.

The amazing collision of oncolytic bacteria and ADCs: YB1 tumour immunotherapy comes out of nowhere

However, traditional antibody-drug couples also have limitations, such as low concentrations of tumour targets relative to the drug and rapid drug metabolism and short half-lives. Combining with other vectors that are more tumour-targeting, may be a way to address the limitations of traditional ADC drugs.

The company has invented its own large-molecule drug delivery vector, YB1, which can carry ADC drugs. This combination of oncolytic bacteria and ADC can be expressed through the internal gene regulation of YB1, and the presentation of antibody sequences to The company has laid out a corresponding product pipeline, YB1-ADC, for the indication of Her2 positive breast cancer, which is currently in preclinical development.As a technology-based innovative R&D company focused on biomolecule drug delivery platforms, our core product is the biomolecule drug delivery vehicle YB1.

YB1 has now made a major research breakthrough in cancer treatment, which can precisely identify the hypoxic zone of tumours, and after intravenous injection, with a limit of 0.5% oxygen concentration, YB1 can be rapidly cleared in normal organs. It can achieve targeted aggregation and proliferation in the hypoxic zone of tumours, and further release the drugs it carries to exert a tumour lytic effect.

Other versions of YB1 also excel in thrombosis treatment, automatically identifying the location of thrombosis through haemodynamics, locating the hoarding and releasing the thrombolytic drug at the right point.

Research has proven that YB1 is a powerful delivery agent that can efficiently deliver various large molecule anti-cancer drugs such as protein drugs, mRNA vaccines, antibody drugs, oncolytic viruses, etc. The future development prospects in the clinical application market are promising, and the combination with ADC is also an innovation in the field of cancer treatment. And we hope to create more surprises in the future to contribute to the global anti-cancer cause.

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