Target-specific therapies are reshaping the healthcare landscape, providing a promising solution to treat cancer. The therapies involve monoclonal antibodies that induce the immune system to initiate an action against infection and disease, thereby killing the cells. Despite its significant role in cancer treatment, monoclonal antibodies have low binding efficiency and lead to toxicity in normal cells. To address the concern, antibody-drug conjugate emerges as the next-generation target-specific therapy for the treatment of cancer. It combines small molecule cytotoxin, monoclonal antibodies, and linkers that efficiently deliver the cytotoxin inside the tumor cells without causing damage to normal cells.
To date, the approved ADCs have been used for the treatment of urothelial cancer, cervical cancer, multiple myeloma, ovarian cancer, and breast cancer. The increasing number of patients with cancer at the global level raises concern about finding more antibody-drug conjugates for the treatment. Around 14 antibody-drug conjugates are approved by the FDA for the treatment of cancer. Besides this, the ADC market players, including Pfizer and Seagen, are actively engaged in developing more ADCs by leveraging advanced technologies and genetic engineering. Driven by the above factors, it is expected that the global Antibody drug conjugate market will grow at a CAGR of 9.63% in the future, according to Roots Analysis.
Antibody Drug Conjugates- The New Frontier of Cancer Treatment
Antibody drug conjugates have a potent cytotoxic anticancer agent, which is linked to the antibody via a biodegradable linker. The antibodies bind directly to the specific antigens or receptors available at the surface of cancerous cells. Antibody-drug conjugate formed with the linker internalized into the cancer cell and released the drug. The mechanism of action of ADC is simple and focused on delivering cytotoxic agents inside the tumor cells, maximizing the therapeutic index, and reducing exposure to normal tissues. The cell lysis begins when ADC reaches the target site and releases the payload.
Antibody Drug Conjugates Approved For the Treatment
The targeted delivery of cytotoxic compounds into the tumor cells is a strategic approach to treating cancerous patients. However, the development of antibody-drug conjugates poses considerable challenges for the antibody-drug conjugate market players. With persistent research and technological advances, several market players, including Pfizer, Seattle Genetics, and more, have successfully secured approval of the below-listed ADCs from the FDA.
Table: List of Antibody Drug Conjugates Approved By FDA For The Treatment
Company Name
Trade name
ADC Drug
Target
Payload Action
ImmunoGen
ELAHERE®
Mirvetuximab soravtansine
FRα
Folate receptor alpha
Seagen
Tivdak®
Tisotumab vedotin-tftv
Tissue factor
microtubule inhibitor
Seagen
Tivdak®
Tisotumab vedotin-tftv
Tissue factor
microtubule inhibitor
ADC Therapeutics
Zynlonta®
Loncastuximab tesirine-lpyl
CD19
DNA cleavage
Immunomedics
Trodelvy®
Sacituzumab govitecan
TROP2
TOP1 inhibitor
AstraZeneca/Daiichi Sankyo
Enhertu®
Trastuzumab deruxtecan
HER2
TOP1 inhibitor
Astellas/Seagen Genetics
Padcev®
Enfortumab vedotin
Nectin4
microtubule inhibitor
Genentech, Roche
Polivy™
Polatuzumab vedotin-piiq
CD79
microtubule inhibitor
Astrazeneca
Lumoxiti®
Moxetumomab pasudotox
CD22
–
Pfizer/Wyeth
Besponsa®
Inotuzumab ozogamicin
CD22
DNA cleavage
Genentech, Roche
Kadcyla®
Trastuzumab emtansine
HER2
microtubule inhibitor
Seagen Genetics, Millennium/Takeda
Adcetris®
Brentuximab vedotin
CD30
microtubule inhibitor
Pfizer/Wyeth
Mylotarg®
Gemtuzumab ozogamicin
CD33
DNA cleavage
In addition to the above-listed ADCs, more than 70 Antibody drug conjugates are either approved by the FDA or under clinical trials for the approval. So, there will be a hope of getting more ADCs to be approved for the treatment of chronic diseases in the upcoming years.
Antibody Drug Conjugates: Advancements for Better Oncology Treatment
In some cases, antibody-drug conjugate development leads to failure due to on-target toxicity associated with the expression of the targets on tissues and lack of efficacy even after achieving the maximum tolerated dose. The on-target toxicity is a rare cause of discontinuation of ADC due to insufficient efficacy.
Thus, to maximize the success rate of antibody-drug conjugate development, an advanced framework is required, emphasizing keen selection and combination of ADC prime components. A strategic approach has been adopted by the ADC market players for the optimization of targets, linkers, antibodies, and payloads to ensure patients get complete benefits from the treatment. Below are the advanced approaches followed by pharmaceutical companies to craft highly effective ADCs for cancer treatment.
§ Site-Specific Conjugation of Antibody Drug Conjugates
With the availability of advanced tech-driven solutions, it is possible to engineer Antibody drug conjugates with site-specific conjugation. Aldehyde tag (a six amino acid sequence) that can be genetically encoded into specific locations of antibody constant regions.
The amino acid sequences act as a substrate for the form of a glycine-generating enzyme that can convert a cysteine residue into the tag sequence containing aldehyde functionality. There are multitudes of locations present on the antibody that can easily be modified with an advanced solution without altering the biophysical properties. The aldehyde tag provides flexibility in payload placement that further brings opportunities for the optimization of conjugates, leading to higher yield.
§ SMARTag Tandem- Cleavage Linkers for Better ADC Stability
Antibody-drug conjugate companies commonly incorporate substrates for acid-mediated hydrolysis, protease cleavage, and disulfide reduction for designing cleavable linkers. This approach leads to poor stability of ADC as they have only a single lock to protect conjugate integrity. The cleavable linkers share a common element, and only one cleavage is needed to release the payload, resulting in loss of payload, reduced efficacy, and more toxicity.
To address this challenge, ADC market players have adopted the SMARTtag Tandem linker system that aims to enhance the stability in circulation, thereby increasing the therapeutic index. The innovative design of ADC incorporates two locks simultaneously for the protection of the payload. The first lock, which is a valine-alanine dipeptide, acts as a substrate for the protease, and the second lock includes the placement of glucuronic acid associated directly with the dipeptide. The cleavage component helps to enhance the versatility and is easily incorporated into different cleavable linker systems for better stability of antibody-drug conjugates.
§ Dual Loaded ADCs
Presently, the ADC market is focused on designing conditionally activated Bispecific antibody-drug conjugates with an aim to enhance the specificity at the tumor cell site and reduce toxicity in normal tissues. The conditionally activated antibody-drug conjugates reduce on-target toxicity by using high protease activity within the tumor cell environment.
What’s Next in the Antibody Drug Conjugate Market?
Overall, the success of Antibody-drug conjugate as a therapeutic molecule has substantially channelized the pathway for future research and development. With ongoing research and clinical trials, scientists are going beyond boundaries, leveraging technology to provide more effective, precise, and personalized ADCs for cancer treatment. Thus, the future of the antibody-drug conjugate market is promising and expected to receive steady growth in upcoming years.
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