In the field of targeted delivery of drug conjugates, the concept of the magic bullet was proposed more than a hundred years ago. Magic bullet drugs can specifically identify and kill cancer cells without harming normal cells. With the continuous progress of protein genetic engineering, chemical conjugation and other technologies, the field of targeted delivery of drug conjugates is not limited to antibody drug conjugates, and most structures with specific targeted effects can be used as carriers of small molecule toxins. In recent years, the scope and application scenarios of drug conjugates, including multiple concepts such as combination medication and precise drug delivery, have continued to expand, and a variety of emerging conjugation technology concepts have emerged one after another.

In general, the research and development of 9 types of drug conjugates are favored by relevant institutions and enterprises.

01 Antibody Drug Conjugates (ADC)

ADC, also known as "biomissile", is a drug that combines cytotoxic drugs similar to chemotherapeutic drugs with monoclonal antibodies to achieve targeted killing of tumor tissue. ADC drugs consist of three parts: antibodies, linkers, and effector molecules (small molecule cytotoxic drugs). The global ADC drug market is expected to reach $20.7 billion in 2030, with the domestic market reaching $4.2 billion, according to Frost Sullivan.

As of December 2021, a total of 14 ADC drugs have been approved for marketing, and more than 400 announced ADC drug candidates are under development, mainly in the fields of cancer, rare diseases and hematologic diseases. There are 136 drug candidates that focus on common targets, 53 of which target HER2.

The ADC drug is injected into the blood circulation, and its antibody part specifically binds to the antigen on the surface of the tumor cell, and the complex formed by the binding is engulfed by the cell. In cells, cleavable linkers are sensitive to environmental factors in tumor cells and will be cleaved by specific pH environment, proteases, or certain chemicals. ADC drugs carrying non-cleavable linkers are digested by lysosomes, thereby release the drug. Small molecules of certain ADC drugs can penetrate cell membranes to further kill surrounding cancer cells, a bystander-killing effect. In addition, ADC also has the immune effect of CDC, ADCC, ADCP and other antibodies.

02 Polypeptide Drug Conjugates (PDC)

The principle of PDC is to couple cell-targeting peptides with drug molecules to enhance the targeting of the drug, so that the drug is concentrated in the target tissue, thereby reducing its relative concentration in other tissues, improving effectiveness and reducing adverse reactions. The peptides used in PDC can be divided into two categories: cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs), which have high affinity for receptors overexpressed on the surface of tumor cells.

PDC integrates the advantages of peptides, has a low molecular weight (generally less than 3kD), is biodegradable, and does not cause immunogenic reactions. PDC can change the hydrophobicity and ionization properties of the conjugate by modifying the amino acid sequence of the peptide chain, solve the problems of poor water solubility and untimely metabolism, and at the same time promote cell penetration, avoiding the need for small molecule drugs due to poor physicochemical properties in clinical development. The failure rate is higher in this difficulty. In addition, low molecular weight PDCs are easier to purify by HPLC (high performance liquid chromatography) techniques, which are also critical in pharmacokinetics.

03 Antibody Fragment Drug Conjugates (FDC)

Antikor Biopharma pioneered the development of FDC. Unlike whole monoclonal antibodies used in ADCs, FDCs conjugate antibody fragments to cytotoxic drugs. Due to the small molecular weight of the antibody fragments, the tumor penetration of FDC is better. In addition, the half-life of FDC is also shorter than that of ADC, which can reduce its exposure in normal tissues and better control toxic side effects. The OptiLink technology established by Antikor can systematically analyze and improve the linker between antibody fragments and toxins. By changing the chemical structure and length of the linker and adding PEG polymers to the conjugated drug, the toxin/antibody fragment loading ratio (DAR), druggability, efficacy and safety of FDC can be precisely regulated.

04 Immunostimulatory Antibody Conjugates (ISAC)

In December 2020, in an article published in Nature Cancer, researchers from Bolt Biotherapeutics and Stanford University School of Medicine reported an ISAC. ISACs consist of tumor-targeting mAbs coupled to immune agonists through a non-cleavable linker, and can combine the tumor-targeting precision of antibodies, the killing potential of the innate and adaptive immune systems into a single drug, in multiple achieved complete tumor regression and durable antitumor immunity in a variety of tumor models. Overall, the novel ISAC therapy has strong preclinical antitumor activity. ISAC representative drug BDC-1001 is currently undergoing phase II clinical trials in patients with HER2-expressing tumors.

05 Antibody Biopolymer Conjugates (ABC)

Ophthalmology-focused Kodiak Sciences, leveraging its proprietary ABC technology platform, is developing anti-VEGF-macromolecular phosphorylcholine polymer conjugate KSI-301 for the treatment of wet age-related macular degeneration and diabetic macular edema and retinal vein occlusion, currently in phase III clinical trials. By conjugating biopolymers to antibodies, the company extends the half-life of drugs in the eye, greatly reducing the frequency of injections and improving efficacy.

06 Small Molecule Drug Conjugates (SMDC)

The research and development of SMDC, which is very similar to ADC, is still advancing in a stumble, and its related research has not yet achieved breakthrough progress. The number of companies deploying this research and the abundance of targets are far from ADC. SMDC and ADC have a similar composition, and both are composed of targeting molecules, linking arms, and effector molecules (cytotoxic, E3 ligase). The most direct difference between SMDC and ADC is the targeting molecule: ADC uses biological antibodies as drug targeting, while SMDC uses small molecule targeting. Compared with antibody drugs, SMDC is easier to control the synthesis process and cost, and the industrialization operation is simple. SMDC will not have immunogenicity in theory, and safety control is easier to achieve; in solid tumors, SMDC has good cell penetration and Good in vitro and in vivo stability.

07 Radionuclide Drug Conjugates (RDC)

RDCs are primarily composed of antibodies or small molecules, linkers, chelators, and cytotoxic/imaging factors (radioisotopes) that mediate targeting. The targeting of antibodies or small molecules (including peptides) is used to achieve the purpose of precise radiotherapy, which can kill tumors at high doses while reducing radiation to normal tissues, thereby reducing side effects. The biggest difference between RDC and ADC and SMDC is the drug load. RDC is no longer a small molecule, but a radionuclide. Using different medical radionuclides can play different imaging or therapeutic effects, and some radionuclides have both capabilities.

08 Virus-like Drug Donjugates (VDC)

VDC is coupled to a potent cytotoxic drug that can be activated by infrared light. The activated VDC can generate high levels of singlet oxygen, selectively destroy tumor cells, resulting in acute necrosis of tumor cells, while immunogenic cells Death can activate the immune system to produce an antitumor response. This dual mechanism of action can be used for early treatment of primary lesions and can generate durable anti-tumor immune responses to prevent distant metastasis of cancer cells. AU-011 is the leading candidate VDC therapy in Aura's pipeline for the first-line treatment of choroidal melanoma. It has been granted Fast Track and Orphan Drug designation by the U.S. Food and Drug Administration and is currently in Phase II clinical trials.

09 Antibody-siRNA conjugates (ARC)

The scientific research of using antibodies to deliver siRNA can be traced back to 15 years ago when Harvard professor Judy Lieberman and her team expressed Protamine fused with antibodies, and then loaded the negatively charged siRNA with the positively charged Protamine. With the increasing maturity of the technology, Genent Ech used Thiomab technology to specifically conjugate siRNA delivery in 2015, the first attempt to conjugate siRNA directly to antibodies, and showed the effect of intratumoral delivery and gene silencing in a mouse tumor model.

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