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In recent years, significant breakthroughs have been made in the development and treatment of small cell lung cancer (SCLC), with the development of Delta-like ligand 3 (DLL3)-targeted bispecific antibodies and antibody-drug conjugates (ADCs) emerging as a key focus. DLL3 is highly and specifically expressed on the surface of SCLC and neuroendocrine tumor cells, with minimal expression in normal tissues, making it a highly promising target for innovative therapies. Currently, leading pharmaceutical companies such as Amgen and AbbVie are accelerating clinical research on DLL3-targeted drugs, with multiple pipelines advancing to critical stages.
On January 2, 2025, Innovent Biologics announced a global exclusive collaboration agreement with Roche, licensing the worldwide rights of its DLL3-ADC candidate IBI3009 to Roche. Under the agreement, Innovent will receive an upfront payment of $80 million, up to $1 billion in potential development and commercialization milestone payments, and tiered royalties based on global annual net sales.
IBI3009 is developed using Innovent's next-generation camptothecin-based ADC platform NT3
IBI3009 has obtained IND approvals in Australia, China, and the United States, with the first patient successfully enrolled, and clinical studies are actively underway. As a highly anticipated DLL3-ADC candidate, IBI3009 was not developed using the previously utilized Lonza Synaffix platform but was instead designed on Innovent’s proprietary next-generation camptothecin-based ADC platform, NT3. This platform employs the novel topoisomerase I inhibitor (TOPO1i) Exatecan as the payload, leveraging structural optimization and advanced conjugation technology to enhance the efficacy and safety of ADC therapeutics. Studies have shown that Exatecan-based ADCs demonstrate significantly improved antitumor activity and reduced off-target toxicity compared to traditional payloads such as MMAE/MMAF, particularly in treating highly heterogeneous tumors such as gastric, lung, and breast cancers. With higher DAR and superior potential tumor-killing efficiency, IBI3009 offers a promising new treatment option for patients with refractory tumors.
On October 3, 2024, according to a PCT update, Innovent Biologics disclosed patent WO2024208359 for the first time, covering its independently developed next-generation camptothecin ADC platform, NT3, and its applications. The patent details the development of a novel HER2-ADC drug using camptothecin derivatives as cytotoxic payloads. This approach aims to target specific cancer cell antigens and deliver camptothecin derivatives directly to cancer cells, enhancing therapeutic efficacy while minimizing systemic toxicity.
Innovent's HER2 camptothecin-based ADC demonstrates superior in vitro activity compared to Daiichi Sankyo's DS-8201.
In the N78 model, the HER2 camptothecin-based ADC exhibits superior in vivo activity compared to Daiichi Sankyo's DS-8201
The pharmacokinetics and toxicity risks of the PL1 constructed HER2 camptothecin ADC are similarly low compared to DS-8201
Innovent Biologics, leveraging its NT3 self-toxin platform, has developed 20 camptothecin derivative toxins. Among them, the PL1 toxin utilizes traditional cysteine conjugation with a DAR value of 8. As shown in figures uphold, the HER2 camptothecin ADC constructed by Innovent demonstrates superior in vitro activity compared to DS-8201 from Daiichi Sankyo. In the N87 model, the PL1-constructed ADC also shows significantly better anti-tumor efficacy than DS-8201. However, both the PL1-based ADC and DS-8201 exhibit similar pharmacokinetic profiles and low toxicity risks.
At the beginning of 2025, the landmark partnership between Roche and Innovent highlights Roche's multi-path strategy in SCLC drug development. First, Roche's DLL3-targeted trispecific antibody, RG6524, serves as an upgraded version of the bispecific antibody. While both target DLL3, RG6524 and DLL3-ADC IBI3009 differ in their mechanisms of action. Both RG6524 and IBI3009 can be combined with PD-L1 antibodies, forming two complementary treatment approaches. Secondly, DLL3 is a key therapeutic target in SCLC. Although AbbVie's DLL3-ADC previously failed, this was mainly due to limited understanding of the toxin and ADC at the time. Current clinical data suggests that TOPO1i toxins are more ideal, offering low toxicity and bystander effects, which enhances their drug development potential. Finally, while Roche's RG6524 trispecific antibody shows better efficacy than bispecific antibodies in preclinical studies, TCE antibodies carry the risk that higher efficacy may lead to greater toxicity. Therefore, even if RG6524 fails in clinical trials, IBI3009 remains a viable alternative, ensuring Roche's ongoing development and deeper positioning in DLL3-targeted therapies.
To meet the development needs of DLL3-targeted small cell lung cancer ADCs and antibody drugs, ACROBiosystems has developed the following:
• High-Quality DLL3 Recombinant Proteins: Expressed in human cells and verified by SEC-MALS, ELISA, SPR, and BLI, these proteins are characterized by high purity, high activity, and excellent batch-to-batch consistency, making them suitable for immunology, antibody screening, and candidate drug function validation.
• High-Quality DLL3 Overexpressing Cell Lines (CHO, HEK293): The antigen is stably expressed on the surface of host cell membranes, meeting the needs for antibody drug activity screening (cell-level binding and blocking) and evaluation of CAR molecule cytotoxicity.
ACROBiosystems performs batch-by-batch quality control on all products, verifying properties such as purity and binding activity, and provides free protocols with experimental parameters and procedures developed by our research team to help you save R&D time.
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