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Fumbling forward: Inventory the upgrade path of ADC connectors

 Last Update: 2022-08-15
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According to a December 2021 report by business consulting firm IMARC group, the global market for Antibody-drug conjugates (ADCs) will reach $1 billion in 202 It is expected that in the next five years, this number will continue to grow at an ultra-high growth rate of 28% per ye.

On the one hand, it is because of the accumulation of continuously updated technologies and experience that ADC drugs have broken through the previous bottlenecks, and on the other hand, it is also because the excellent clinical data of the new generation of ADC drugs has ignited the enthusiasm of practitione.

As of September 2021, 15 ADC drugs have been launched in the world (Table 1), and more than 350 are in the clinical research sta.

Table 1 Global marketed ADC drugs1

Technological accumulation and breakthroughs are reflected in many aspec.

ADC transforms the small molecule cytotoxic drugs that were originally "indifferent between good and evil" into an army of "distinguishing loyalties.

FigureThe structure of the ADC and the schematic diagram of the functions of each pa.

The transition from mouse to human is more and more diverse More than 80 models from "crack" to "no crack" to "better crack"

Linkers in listed ADCs

The tortuous first-generation ADC drug Mylotarg® uses a cleavable linker containing an acid-sensitive hydrazone bond and a GSH-sensitive disulfide bo.

FigureSchematic diagram of the AcBut linker based on hydrazone and disulfide bonds in Mylotarg® 2 The second generation ADC represents a drug with a maleimide (MC) structure added to the link.

If a cleavable linker is a "slip knot" that can be opened, then a non-cleavable linker is a "dead knot" that cannot be opene.

FigureExample 2 of a maleimide-based link.

The MC linker can also be used as a spacer to participate in the design of cleavable linke.

In 2017, the third-generation ADC drug Besponsa® was approved for marketing for the treatment of acute lymphoblastic leukem.

In addition to hydrazone bonds and disulfide bonds, dipeptide linkers are widely used in third-generation ADC dru.

That is to say, the peptide linker is equivalent to a reinforced "slip knot" ,

Padcev® and Polivy®, which were approved for marketing in 2019, use the same valine-citrulline dipeptide linker (Val–Cit) as Adcetris®; IMGN632, which was approved as a breakthrough drug in 2020, uses alanine-alanine Acid dipeptide linker (Ala–Ala); Zynlonta® approved in 2021 uses a valine-alanine dipeptide linker (Val–Al.

In 2019, T-Dxd (trade name Enhertu®) was approved for marketing for the treatment of unresectable or metastatic Her2-positive breast canc.

In addition to the preference for peptide linkers, another milestone in the conjugation strategy of third-generation ADC drugs is the use of site-specific conjugation technology, such as Enhertu®, Padcev® approved in 2019, and .

The early ADC preparation process can be compared to the process of hanging small decorations on a Christmas tr.

The Christmas tree represents antibodies, and the small decorations represent small-molecule dru.

We know that the small decorations are randomly decorated on the Christmas tree, and different people have different decorations on the Christmas tr.

Similarly, in the early ADC preparation, the coupling site of small molecule drug and antibody is uncertain, and DAR is also difficult to determi.

As a result, the produced ADCs are highly heterogeneous mixtures with poor stability and non-uniform quality, making it difficult to achieve effective quality and efficacy contr.

Using fixed-point coupling technology to prepare ADC, returning to the previous analogy, is like asking workers to produce a batch of identical Christmas trees according to the standard process, and the number and position of the trinkets are determin.

That is to say, the site-specific coupling technology enables antibody and small molecule drugs to be site-specific and quantitatively coupled, with high homogeneity, good stability, convenient large-scale preparation, and better activi.

Fixed-point coupling will gradually become the main theme of the ADC fie.

At present, there are many ways to achieve the site-directed coupling of ADCs, including site-directed coupling that introduces unnatural amino acids, enzyme-catalyzed site-directed coupling, N-glycosylation site-based site-directed coupling, and reactive half-based conjugati.

Site-directed coupling of cystine and tyrosine,e.

In addition to the above-mentioned linkers, the development of new linkers is also in full swing, such as β-galactosidase-responsive linkers, phosphatase-responsive linkers, and sulfatase-responsive linkers, e.

In the rapid rise, many drugs are in the clinical research stage, and the future can be expect.

Epilogue

In June 2021, the first domestic ADC drug Vidicitumumab was approved for marketing, and Rongchang Biotech, which developed the drug, became a pioneer of domestic ADCs in one fell swo.

In the face of huge clinical demand and market prospects, many domestic pharmaceutical companies including Hengrui Medicine, TOT BIOPHARM, Doxi Bio, Kelun Botai, Genting Xinyao, e.

have been gearing up and actively deploying, and ADC drugs have become a Following the next R&D outlet of PD-1/PD-L Looking forward to the ADC track in the future, domestic and foreign pharmaceutical companies will compete for the first place, and it will be exciti.

We will wait and see who can write the next lege.

references:

Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Revi.

https:// Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Revi.

https://Kang, MS, Kong,.

, Khoo,.

, & Loh, TP (202
Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody-drug conjugat.

Chemical science, 12( 41), 13613–1364

Kang, MS, Kong,.

, Khoo,.

, & Loh, TP (202
Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody-drug conjugat.

Chemical science, 12( 41), 13613–1364

Baah,.

, Laws,.

, & Rahman, KM (202
Antibody-Drug Conjugates-A Tutorial Revi.

Molecules (Basel, Switzerland), 26(10), 294

Bargh, JD, , Isidro-Llobet,.

, , Parker, JS, , & Spring, DR, (201
Cleavable linkers in antibody-drug conjugat.

Chemical Society reviews, 48(16), 4361–437

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