Antibody Drug Conjugates Dominating Clinical Trials Targeting CD276

Release Date: 17-Feb-2023

Antibody drug conjugates have become the fastest growing drug class in the global pharmaceutical market. Combining the targeting ability of a monoclonal activity with the cytotoxic action of anti-cancer drugs in one molecule, they have emerged as a feasible method to treat cancer. Connected by a linker, the three components comprise a highly effective anti-tumor agent directly and selectively providing chemotherapy drugs to cancer cells, directed by antibodies with exceptional specificity and affinity. The CD276, which plays a dual role in the immune system, has emerged as one of the newest targets for antibody-drug conjugates, many candidates having cleared initial phases of clinical trials,


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The CD276 is an immune checkpoint which plays the double roles of an inhibitor and an immune stimulator and has found potential uses in the treatment of several diseases affected by the immune system. The clinical and developmental pipelines of the drugs target the CD276 is well dominated by antibody-drug conjugates. Moreover, results from completed clinical trials have revealed promising results which have supported the applicability of these in the treatment of cancers overexpressing the CD276. 


Omblastys (Omburtamab/131I) is an antibody-drug conjugate farthest in clinical trial. It consists of a theranostic monoclonal antibody named 8H9 linked to 131 Iodine and is being evaluated in patients with solid tumors. However, its clinical trial in pediatric patients with neuroblastoma that has metastasized to the CNS or leptomeninges is now undergoing a pivotal phase II study. Ifinatamab Deruxtecan is another antibody-drug conjugate targeting the CD276 protein which was developed as part of a strategic research collaboration between Daiichi Sankyo and the Sarah Cannon Research Institute.


Ifinatamab Deruxtecan was created utilizing the DXd ADC technology, which is a proprietary of Daiichi Sankyo and is used to target and deliver a cytotoxic payload into cancer cells that express a certain cell surface antigen. The monoclonal antibody in this specific antibody-drug conjugate is linked to a range of topoisomerase I inhibitor payloads via cleavable linkers based on tetrapeptides. For extensive-stage small-cell lung cancer, the candidate has enrolled in phase II clinical study, which is scheduled to end in November 2024.


Due to its role in tumor cell metabolism, migration, and invasion, angiogenesis, chemotherapy resistance, endothelium to mesenchymal transition, and expression on cancer-initiating cells, B7-H3 has garnered a great deal of interest. Although CAR-T treatments that target the protein have also been tried, antibody-drug conjugates have demonstrated superior anti-cancer activity. Antibody-drug conjugates have undergone several improvements in the last several years which has allowed the generation of better quality antibodies. New generation antibody-drug conjugates are exhibiting increasingly ideal specificity and cytotoxicity profiles compared to early generations. However, there are still several obstacles to overcome in the creation of anti-cancer antibody-drug conjugates, including structural complexity, drug resistance, and insufficient tumor targeting and payload release. These need to be addressed to allow the development of more efficient antibodies targeting the CD276. 


The internalization and the intracellular transit channels of antibody-drug conjugates have been proven to have a significant influence on its ability to cause cell death. Moreover, the development of bispecific antibody platforms has expanded the potential for novel antibody-drug conjugates. In preclinical tests, a bispecific ADC demonstrated improved lysosomal agglomeration and load delivery. Similarly, to lessen drug resistance, a dual-payload antibody-drug conjugate that uses two different cytotoxic chemicals as payloads can be generated. Delivering two co-ordinated payloads to cancer cells could result in a greater robust effectiveness by precisely regulating the quantity of the two drugs. To increase the therapeutic effects of antibody-drug conjugates, improvements like these are crucial and are the need of the hour considering how CD276-targeting is still in its infancy despite it being discovered more than two decades ago.

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