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Release date:2024/5/10 16:49:05

The concept of antibody-drug conjugates (ADCs) was first described as a “magic bullet” by Dr. Paul Ehrlich in 1913. This concept involves attaching cytotoxic drugs to specific monoclonal antibodies to achieve targeted killing of tumor cells. Previously, the synthesis of ADCs faced significant hurdles due to high technical barriers and persistent challenges like off-target effects and identifying specific antigens. It wasn't until 2000 that the FDA approved the first ADC, Mylotarg, developed by Pfizer, for treating acute myeloid leukemia.

According to statistics, there are currently 15 ADC drugs approved globally, with over a hundred more undergoing clinical research. ADCs have evolved from late-stage treatment for specific blood cancers to potentially treating a broader range of solid tumor indications and offering early treatment options for other diseases. Future ADC drug development will mainly focus on expanding indications and treatment lines, as well as exploring combination therapies with other treatment modalities.

In 2024 or 2025, three ADCs are expected to receive FDA approval: AstraZeneca/Daiichi Sankyo's Datopotamab Deruxtecan (Dato-DXd), Daiichi Sankyo and Merck's patritumab deruxtecan (HER3-DXd), and AbbVie's Telisotuzumab vedotin (ABBV-399).

Datopotamab Deruxtecan (Dato-DXd,DS-1062)

Datopotamab Deruxtecan (Dato-DXd, DS-1062) is a TROP2-directed DXd ADC, jointly developed by AstraZeneca and Daiichi Sankyo. Trop-2 is highly expressed in various malignant solid tumors, including breast cancer, with nearly no expression in normal tissues. In breast cancer, the positivity rate is as high as 78%, reaching up to 95% in TNBC.

Datopotamab-deruxtecan

Figure 1. Structure of Datopotamab Deruxtecan

On February 19, 2024, Daiichi Sankyo/AstraZeneca jointly announced that their Biologics License Application (BLA) for datopotamab deruxtecan had been accepted by the FDA for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in adult patients who have previously received systemic therapy. The Prescription Drug User Fee Act (PDUFA) date is December 20, 2024.

The BLA is based on results from the pivotal TROPION-Lung01 Phase III trial in which datopotamab deruxtecan demonstrated a statistically significant improvement for the dual primary endpoint of progression-free survival (PFS) compared to docetaxel, the current standard of care, in patients with locally advanced or metastatic NSCLC treated with at least one prior line of therapy.

As presented in a Presidential Symposium at the ESMO Congress 2023, median PFS was longer with the datopotamab deruxtecan than with docetaxel (4.4 months versus 3.7 months) in previously treated patients with advanced non-small-cell lung cancer (NSCLC) (LBA12). Interim data for the co-primary endpoint of overall survival (OS) were 12.4 months with datopotamab deruxtecan and 11.0 months for docetaxel (HR 0.90; 95% CI 0.72–1.13). Confirmed objective response rates (ORR) were 26.4% with datopotamab deruxtecan and 12.8% with docetaxel, with median durations of response of 7.1 months and 5.6 months, respectively. 

tropion-lung01

Figure 2. Median PFS was significantly longer with datopotamab deruxtecan than with docetaxel in the TROPION-Lung01 trial

Patritumab Deruxtecan (HER3-DXd) 

Patritumab Deruxtecan (HER3-DXd), jointly developed and commercialized by Daiichi Sankyo and Merck, is a potential first-in-class DXd ADC targeting HER3, designed using Daiichi Sankyo's proprietary DXd ADC technology. It is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

 

HER3-DXd
Figure 3. Structure of Patritumab Deruxtecan

On December 22, 2023,  Daiichi Sankyo and Merck announced that the FDA has accepted and granted Priority Review to the BLA for patritumab deruxtecan for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC previously treated with two or more systemic therapies. The PDUFA date is June 26, 2024. The Priority Review follows the receipt of the Breakthrough Therapy Designation granted by the FDA in December 2021.

The BLA is based on the primary results from the HERTHENA-Lung01 pivotal phase 2 trial and data results presented at the IASLC 2023 World Conference on Lung Cancer (#WCLC23).

Findings from the HERTHENA-Lung01 showed that treatment with the patritumab deruxtecan led to an overall response rate (ORR) of 29.8% (95% CI, 23.9%-36.2%) by blinded independent central review (BICR), with 1 complete response, among patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR-directed TKI and platinum-based chemotherapy (n = 225). Additionally, the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8), and the median progression-free survival (PFS) was 5.5 months (95% CI, 5.1-5.9).

HERTHENA-Lung01

Figure 4. HERTHENA-Lung01 results

Telisotuzumab vedotin (Teliso-V, ABBV-399)

Telisotuzumab vedotin (Teliso-V, ABBV-399) is an internally developed c-Met ADC by AbbVie. It's currently the only c-Met ADC in Phase III clinical trials worldwide. Previously, it received orphan drug designation and breakthrough therapy designation from the FDA. ABBV-399 is composed of the anti-c-Met monoclonal antibody ABT-700 linked to MMAE through a cleavable dipeptide linker, with a DAR value of 3.1.

On November 29, 2023, AbbVie released top-line findings from the single-arm Phase 2 LUMINOSITY trial, which investigated telisotuzumab-vedotin in patients with overexpression of c-Met protein, wild-type EGFR, and advanced/metastatic nonsquamous (NSCLC). The results revealed a notable overall response rate according to independent central review (ICR) of 35 percent and 23 percent among patients with high and intermediate levels of c-Met, respectively.

Moreover, other key endpoints demonstrated clinically significant outcomes, including a median duration of response per ICR of 9 months and 7.2 months, as well as a median overall survival of 14.6 months and 14.2 months for patients with high and intermediate levels of c-Met, respectively.

On Nov. 30, 2023, AbbVie Inc. and ImmunoGen, Inc. announced a definitive agreement under which AbbVie will acquire ImmunoGen, and its flagship cancer therapy ELAHERE® (mirvetuximab soravtansine-gynx), a first-in-class ADC approved for platinum-resistant ovarian cancer (PROC). The acquisition accelerates AbbVie's commercial and clinical presence in the solid tumor space. Additionally, ImmunoGen's follow-on pipeline of promising next-generation ADCs further complements AbbVie's ADC platform and existing programs.

AbbVie is moving forward with plans to bring its first ADC drug, telisotuzumab-vedotin, to market, but the specific timing will depend on the results of clinical trials and strategic planning at the corporate level. It is highly likely to occur between 2024 and 2025.

Conclusion

As exploration deepens in the ADC field regarding new targets, mechanisms of action, and new forms of ADCs, its future development path is bound to become broader and longer. It is believed that more and more ADCs will be approved in the future.

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References:
[1] https://dailyreporter.esmo.org/esmo-congress-2023/non-small-cell-lung-cancer/datopotamab-deruxtecan-met-the-pfs-endpoint-in-previously-treated-nsclc
[2] https://www.merck.com/news/patritumab-deruxtecan-granted-priority-review-in-the-u-s-for-certain-patients-with-previously-treated-locally-advanced-or-metastatic-egfr-mutated-non-small-cell-lung-cancer/
[3] https://news.abbvie.com/2023-11-29-AbbVie-Announces-Positive-Topline-Results-from-Phase-2-LUMINOSITY-Trial-Evaluating-Telisotuzumab-Vedotin-Teliso-V-for-Patients-with-Previously-Treated-Non-Small-Cell-Lung-Cancer-NSCLC


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