The Magic Bullet to Cancer in the New Century takes stock of 14 ADCs available worldwide

In recent years, the treatment of tumors has gradually expanded from the "indiscriminate killing" of radiotherapy and chemotherapy to the "precise guidance"
of targeted drugs and immunotherapy.
As early as the beginning of the last century, the idea proposed by the Nobel Prize winner in physiology and medicine, the father of chemotherapy, that is, the "magic bullet" (Magic Bullet) that accurately shoots toxins into tumor cells through a certain carrier, with the development of antibody technology and chemical connection, has also been realized
in the form of ADC in this century.
The powerful efficacy of ADC and the diametrically opposed low toxicity side effects have also become a new research hotspot
in the field of anti-cancer in this era.

What is an ADC?

ADC is an antibody conjugate drug, which, as the name implies, is a drug
made by conjugating antibodies with cytotoxic drugs.
Therefore, the ADC consists of three important components: antibody, linker, and toxin (Drug/Toxin/payload), and then the three are combined
by conjugation technology.

Antibodies: Antibodies are the guidance system of a bullet, and the choice of antibodies is the starting point for
an ADC design.
Tumor targets are the medium for ADCs to recognize tumor cells, and the current selection of ADC targets mainly focuses on proven tumor targets, including HER2, EGFR, CD-19, etc
.
The ADC antibody generally needs to meet the following conditions: has a high affinity with the target; Long half-life; Minimized immunogenicity
.
On the one hand, the binding of antibodies to tumor cells can accurately guide the release of toxins, on the other hand, the binding of antibodies itself can inhibit the downstream signaling of antigen receptors to achieve the tumor suppression effect
of the antibody itself.

Linker: The linker is a bridge between antibodies and toxins, which not only needs to ensure that the ADC finds a stable connection of pretumor toxins to prevent damage to normal cells, but also to ensure that the tumor is quickly released to kill tumor cells
after finding it.
At present, linkers are mainly divided into two categories, split-type linkers and non-splitting linkers
.
The former uses the tumor microenvironment to automatically cleave the toxin of the membrane to kill surrounding tumor cells, that is, the bystander effect; The latter allows toxins to be released
in tumor cells through the specific binding of antibodies to tumor cells.
Both have their own advantages and have different applications
in ADCs.

Toxins: Toxins are the main lethal part of
the bullet.
The toxins currently used are mainly marketed chemotherapy drugs, which can be divided into microtubule inhibitors and DNA damaging agents
according to the killing mechanism.
In addition, some new small molecule drugs have also been used in the development of ADCs, such as RNAII polymerase inhibitors, toll-like receptor agonists, BCL-xL inhibitors, etc
.
The ultimate goal is to kill target cells and cause tumor cell death
.

Therefore, ADC combines the killing effect of toxins through the targeted action of antibodies, ADC can not only improve the therapeutic window and efficacy of targeted drugs, but also reduce the non-targeted toxic side effects of cytotoxic drugs, and at the same time have specificity and high efficiency, reducing the occurrence
of adverse reactions.

Anti-cancer ammunition arsenal - inventory of ADC drugs that have been marketed worldwide

With its good development prospects, pharmaceutical companies in various countries are accelerating the research and development
of ADCs.
Up to now, 14 ADC drugs have been launched
in the world.

1.
Mylotarg

（Gemtuzumab Ozogamicin）

Developed by Pfizer, Mylotarg is the world's first commercially available ADC
.
In order to meet the needs of a large number of patients with acute myeloid leukemia (AML) at that time, Mylotarg was approved by the FDA on May 17, 2000 with only three phase II clinical trial results
.
However, as the first ADC to be rushed to market, subsequent large-scale phase III clinical trials have found that the drug may increase the mortality of patients, which has huge hidden dangers
.
In June 2010, Pfizer announced the voluntary withdrawal of Mylotarg
.
However, the story did not end, and for 7 years, researchers in various countries did not give up on Mylotarg
.
The results of a series of subsequent clinical trials found that while reducing the dose of the drug, it was clear that the drug was only effective
if there was AML with high expression of CD33 protein.
Finally, in 2017, Mylotarg adjusted the original 9mg/m2 to 3mg/m2, and this ADC, which had experienced 17 years of twists and turns, was once again approved by
the FDA.

Mylotarg is structured by conjugating
the DNA lystic agent cachithromycin to an anti-CD33 IgG4 antibody by clearing the hydrazone bond as a lysable linker.
The drug is used to treat newly diagnosed CD33-positive AML in adults, and can also be used in patients with relapsed CD33-positive AML aged 2 years and older or who do not respond to initial therapy, and is the first drug
to be used in pediatric patients.

2.
Adcetris

（brentuximab vedotin）

Adcetris, jointly developed by Takeda Pharmaceuticals and Seattle Genetics, was approved by the FDA in
2011.
Its constituent structure is conjugated by the chimeric antibody IgG1 targeting CD30 and the tubulin inhibitor MMAE via a protease-sensitive linker
, Vat-Cit.
The drug is mainly suitable for classical Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (sALCL), which was approved by the NMPA in China in 2020 for the treatment of patients with relapsed or refractory sALCL and CD30-positive HL, and is the second ADC
approved for marketing in China.

3.
Kadcyla

（Adptrastuzumab emtansine）

Kadcyla, developed by Roche and ImmunoGen, was approved by the FDA on February 22, 2013 for HER2-positive metastatic breast cancer
.
Kadcyla is coupled to humanized IgG1 targeting HER2 by the microtubule inhibitor DM1 through a non-removable thioether bond linker, and is lysosomal through receptor-mediated internalization, so that DM1 degradation products are released in tumor cells leading to apoptosis
.
In 2020, the NMPA was approved for marketing, becoming the first ADC
listed in China.

4.
Besponsa

（Inotuzumab Ozogamicin）

Besponsa was developed by Pfizer for the treatment of acute lymphoblastic leukemia (ALL).

Because ALL is an aggressive leukemia with a poor prognosis, it was prioritized by the FDA for marketing as an orphan drug in 2017, and is currently approved for marketing
in China.
The drug conjugates cachithromycin to anti-CD22 IgG4 antibodies via a clearable hydrazone bond
.
It is suitable for adults with relapsed or refractory precursor B cell ALL, providing a new treatment modality
for relapsed or refractory B cell ALL that was previously difficult to treat.

5.
Lumoxiti

（Moxetumomab pasudotox）

Developed by AstraZeneca, Lumoxiti was approved by the FDA in September 2018 for the treatment of adult patients
with relapsed or refractory capillary leukemia (HCL).
HCL is a rare lymphoproliferative chronic leukemia that progresses slowly but cannot be cured
.
Lumoxiti consists of a cleavable dipeptide linker mc-VC-PABC coupled to an anti-CD22 immunotoxin of Pseudomonas exotoxin
A.
The drug's first approval for the treatment of HCL marks a major advance in
the disease field.

6.
Polivy

（Polatuzumab Vedotin）

Developed by Roche, Polivy is an MMAE conjugate drug targeting CD76β, with antibodies specifically targeting CD76β targets on the surface of B cells and a Vat-Cit
linker.
In June 2019, it was approved by the FDA for the treatment of recurrent or refractory diffuse large B-cell lymphoma
that has received 2 this previous treatment.
Clinical trials have demonstrated a good therapeutic effect
in combination with bendamustine + rituximab.

7.
Padcev

（Enfortumab Vedotin）

Developed by Seagen and Takeda Pharmaceutical, Padcev was approved by the FDA in 2019 for the treatment of advanced or metastatic urothelial carcinoma
.
The drug attaches MMAE to antibodies targeting the cell surface protein Nectin-4
via Vat-Cit.
Nectin-4 is highly expressed in various tumor tissues such as urothelial carcinoma, breast cancer, and gastric cancer, and mediates epithelial mesenchymal transformation, reduces cell adhesion, and enhances tumor aggressiveness
.
The drug has a significant effect on advanced or metastatic urothelial carcinoma and controllable
adverse effects.

8.
Enhertu

（Trastuzumab Deruxtecan）

Enhertu's HER2-targeting antibody-conjugate drug, jointly developed by AstraZeneca and Nihon Daiichi Sankyo, was approved by the FDA in 2019 for the latter-line treatment of HER2-positive breast cancer due to its expansion in 2021 for patients with HER2-positive locally advanced or metastatic gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma treated with trastuzumab
.
The drug consists of
a humanized anti-HER2 monoclonal antibody linked to a topoisomerase-I inhibitor (camptothecin derivative Dxd) via a stable cleavable tetrapeptide linker.
The objective response rate of the drug is significantly higher than that of conventional chemotherapy in patients with HER-positive, advanced gastric or gastroesophageal junction cancer, and overall survival is longer
than conventional chemotherapy.

9.
Trodelvy

（Sacituzumab Govitecan）

Developed by Gilead, Trodelvy was approved by the FDA in 2020 for the treatment of metastatic or advanced triple-negative breast cancer
that is ineffective with at least 2 drug treatments.
Triple-negative breast cancer refers to breast cancer that responds negatively to estrogen receptors, progesterone receptors and HER2 receptors, accounting for about 20% of all breast cancers, and does not respond to
hormone therapy and HER2-targeted drugs.
The drug antibody targets the tumor-associated calcium signaling 2 (TROP-2) receptor, which conjugates to the topoisomerase I inhibitor SN-38 via a hydrolytic linker (pH-sensitive linker) CL2A
.

10.
Blenrep

（Belantamab Mafodotin）

Developed by GlaxoSmithKline, Blenrep was approved by the FDA in 2020 for the treatment of adult patients
with relapsed or refractory multiple myeloma (MM) who have received at least 4 prior therapies.
The drug is a monoclonal antibody targeting the B cell maturation antigen conjugated to the microtubule destroyer monomethylauristatin-F (MMAF), which causes apoptosis
of tumor cells by disrupting microtubule polymerization.

11.
Akalux

（Cetuximab Sarotalocan Sodium）

Developed by Rakuten Pharmaceutical, Akalux was approved by the Japanese Ministry of Health, Labor and Welfare in September 2021 for the treatment of unresectable locally advanced or recurrent head and neck cancer
.
The drug targets the epidermal growth factor receptor (EGFR), which is expressed
on the surface of a variety of solid tumors such as head and neck cancer, lung cancer, esophageal cancer, and pancreatic cancer.
Its toxin is IRDye700DX, which is a photoreactive substance that can activate its pharmacological reaction
by light irradiation.
After the drug and the cancer cells are combined, the near-infrared laser is irradiated to the patient with the BioBlade laser system medical device, and the antibodies in the drug are activated to achieve the purpose of destroying the cancer cells, which is called photoimmunotherapy
.

12.
Zynlonta

（loncastuximab Tesirine）

Developed by ADCTherapeutics, Zynlonta was approved by the FDA in 2021 for adult patients with relapsed or refractory large B-cell lymphoma who have received 2 or more systemic therapies, including diffuse large B-cell lymphoma (DLBCL), DLBCL
originating in low-grade lymphoma, and high-grade B-cell lymphoma.
DLBCL is the most common type of non-Hodgkin lymphoma in the United States, and it is aggressive and rapidly
progressive.
More than 40% of first-line DLBCL treatment failures, with poor
prognosis.
The drug is an ADC that targets CD19, which is a popular target for the treatment of B-cell malignancies
.
Coupling of fully human IgG and DNA lysate SG3199
via lysizable valine-alanine covalent linkers.

13.
Edhi

(vedicitumab)

Edexi is an ADC independently developed by Remegen and the first original ADC in China, which was announced on the NMPA
on June 9, 2021.
The drug consists of antibodies targeting HER2 in combination with Mc-VC-PAB linkers and MMAE
.
Compared with the same type of Kadcyla, the antibody of the drug is a new humanized antibody with high HER2 affinity with independent intellectual property rights, and the linker has intracellular enzymatic hydrolysis characteristics, so the drug has stronger affinity, better safety and stronger tumor cell clearance ability
.

14.
Tivdak

（Tisotumab Vedotin-tftv）

Tivdak is a joint development of Seagen and Genmab and was approved by the FDA on September 20, 2021 for the treatment of patients
with recurrent or metastatic cervical cancer.
Fully humanized IgG
of linker-coupled MMAE with targeted tissue factor (TF) can be cleaved by proteases.

At present, ADC research and development enthusiasm is high, there are more than 400 ADCs in the world in the development of drug candidates, it is believed that more ADCs will shine in the field of tumor treatment in the future
.

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