With the approval of a number of ADC drugs around the world since 2019, conjugated drugs have developed into one of the hottest tracks in the pharmaceutical industry. Not only traditional ADC research and development continues being a hot spot, but also a variety of new drugs conjugates are blooming.
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Peptide-Drug Conjugate
Peptide-Drug Conjugates (PDCs) are composed of a linker, homing peptide, and cytotoxic payload. Targeted peptides can specifically target overexpressed protein receptors on the surface of tumor cells to transmit cytotoxins to induce tumor cell apoptosis. Compared with current ADC drugs, PDC drugs have the characteristics of small molecular weight, strong tumor penetration, low immunogenicity, large-scale synthesis by solid phase synthesis, low production cost, and relatively good pharmacokinetics.
From the perspective of the R&D pipeline, the highest R&D stage in this field is the clinical III phase, and the representative drugs are paclitaxel trevatide (SNG1005) jointly developed by AngioChem and Shennoji, and zoptarelin doxorubicin (AEZS-108) jointly developed by Aeterna Zentaris and Chinese medicine. SNG1005 is a peptide drug coupling that penetrates the blood-brain barrier. Paclitaxel can be specifically delivered to the brain by coupling paclitaxel with amino acid peptides. Phase II clinical results show that SNG1005 has a positive clinical effect in the treatment of pial metastasis of breast cancer and recurrent breast cancer with brain parenchyma metastasis. AEZS-108, a combination of luteinizing hormone-releasing hormone (LHRH) agonist and adriamycin, is currently being tested in castrated, resistant prostate cancer patients.
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Antibody-radionuclide Conjugate
Antibody-radionuclide conjugate representing drugs include Ibritumomab tiuxetan (Zevalin) developed by IDEC Company of Japan. When Zevalin injects a radionuclide-carrying anti-CD20 monoclonal antibody into a patient, it binds to mature B cells and B-cell tumor cells that express CD20, killing them through radiation released by radionuclides. In addition, mirvetuximab soravtansine (MIRV), jointly developed by ImmunoGen and East China, can bind to folate receptor (FR α) and then be transferred into the cell, and the cytotoxic molecule DM4 it carries can inhibit the mitosis of cancer cells and achieve the effect of cancer treatment.
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Antibody-photosensitizer Conjugate
The representative drug of antibody-photosensitizer conjugate, cetuximab sarotalocan (Akalux) developed by Rakuten Medical, was approved by PMDA in September 2020. Akalux is an antibody drug conjugate composed of cetuximab (cetuximab) and IRDye700DX, which can target epidermal growth factor receptors for the treatment of unresectable locally advanced or locally recurrent head and neck cancer. It is the first approved photoimmunotherapy drug in the world.
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Antibody-exotoxin Conjugate
The representative drug of antibody-bacterial exotoxin conjugate is moxetumomab pasudotox developed by AstraZeneca, which is a conjugate of the monoclonal antibody of CD22 and pseudomonas exotoxin (PE38). It has been approved by FDA for the treatment of hairy cell leukemia (hairycellleukemia, HCL). Another representative drug approved is loncastuximab tesirine developed by ADC Therapeutics, which consists of humanized anti-CD19 antibodies and pyrrolobenzodiazepine dimer toxin SG3199, and it was approved by the FDA in April 2021 for the treatment of diffuse large B-cell lymphoma.
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Antibody-biopolymer Conjugate
KSI-301, a representative drug of the antibody-biopolymer conjugate, is developed by Kodiak Sciences. KSI-301 is a new anti-VEGF biological agent developed based on the company’s proprietary ABC technology platform, designed to increase the duration of the drug in eye tissue in order to improve efficacy and reduce the number of injections, and is currently being developed to treat retinal vascular disease and prevent vision loss in patients with diabetic ophthalmopathy. In February 2022, Kodiak Sciences released DAZZLE data for the first registered clinical trial of wet age-related macular degeneration (KSI-301), which showed that visual acuity correction had non-inferiority compared with that of Abuprofen and did not reach the clinical end point. Kodiak Sciences analyzed the result and believed that an important reason for this failure is that the interval dosing regimen is too long. In addition, the BEACON data of the second key clinical trial covering neovascularization age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) are expected to be released in Q3 in 2022.
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Antibody-enzyme Conjugate
The representative drug of antibody-enzyme conjugate is the L-DOS47 targeting CEACAM6 (overexpressed in a variety of epithelial malignant tumors) developed by Helix BioPharma. L-DOS47 is the first targeted therapeutic immunoconjugate developed based on the company’s DOS47 technology, including a highly specialized camel-derived single-domain antibody in which the urease component converts naturally occurring urease to ammonia and is currently being developed for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer.
The representative drug is BDC-1001, developed by Bolt Biotherapeutics, which is a biological analogue of anti-HER-2 trastuzumab, which is coupled with TLR 7 and 8 double agonists through non-degradable connectors for the treatment of HER2 positive solid tumors. In December 2022, Bolt Therapeutics presented the phase 1 clinical data of BDC-1001 at the ESMO conference. Of the 40 assessable patients, 1 case was PR (partial remission) and 12 cases were SD (disease stability). The total remission rate ORR was only 2.5%, and the disease control rate DCR was 32.5%. The performance was not satisfactory.
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Antibody-cell Conjugate
The representative drug of antibody-cell conjugates is ACE1702 developed by Acepodia, which is currently in phase I clinical phase. ACE1702 showed enhanced tumor cell killing activity in studies in vivo and in vitro. At the same time, in the toxicological study of GLP, ACE1702 also maintained good safety.
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Antibody-oligonucleotide Conjugate
The antibody-oligonucleotide conjugate is represented by the drug AOC-1001 developed by Avidity Biosciences. Avidity Biosciences is a pioneer in the development of AOC, which combines the tissue selectivity of monoclonal antibodies with the accuracy of oligonucleotide-based therapy, thereby overcoming obstacles to the transmission of oligonucleotides and genetic drivers of targeted diseases for the treatment of rare muscle diseases and other serious diseases. The first AOC-1001 to enter the clinic consists of three parts: a full-length monoclonal antibody targeting transferrin receptor 1 (TfR1), a linker, and siRNA targeting DMPK mRNA. The indication is myotonic dystrophy type 1 (DM1).
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Antibody-degrader Conjugate
Antibody-degrader conjugate is currently in the early stage of research and development. Its technical principle is to use protein degradants as payload, which has both the tumor specificity of ADC and the applicability of low expression under PROTAC molecular catalytic dose, and can be used in the treatment of solid tumors. The representative drug is ORM-5029 developed by Orum Therapeutics.