Over the past year, the U.S. Food and Drug Administration (FDA) approvals for new antibody-drug conjugates (ADCs) have stalled. Currently, over 80 ADC candidates are in pivotal Phase III clinical trials. Compared to other treatments, ADCs have demonstrated relatively lower risk during development, particularly for a broad range of cancer targets, including breast cancer, non-small cell lung cancer, gastric cancer, and esophageal cancer.

Among the many ADCs in development, several companies are actively seeking unique breakthroughs to stand out. Let's explore these companies' innovative approaches.

Enhertu – Blockbuster ADC

As of now, 15 ADCs have been approved worldwide. Among these, three ADCs targeting HER2 are particularly noteworthy, with the third-generation drug Enhertu making a substantial impact. Since its launch, Enhertu has proven effective in treating HER2-positive breast cancer, gastric cancer, and gastroesophageal junction cancer. It has also expanded its use to HER2-low expressing breast cancer and non-small cell lung cancer.

Table. Approved ADC lists

AstraZeneca is confident in Enhertu's future, anticipating key milestones by 2025, including results from the DESTINY-Breast09 trial for first-line HER2-positive breast cancer and data from the DESTINY-Breast11 trial for high-risk, HER2-positive early breast cancer in the neoadjuvant setting.

Enhertu is not only a core product for AstraZeneca and Daiichi Sankyo but also one of the six major products expected to surpass $5 billion in global sales. Its performance is a key indicator of ADC development trends. Evaluate Pharma projects that Enhertu will achieve peak sales of $10.3 billion, ranking it 16th on the global sales forecast list, with this peak expected by 2028. From 2014 to 2023, Enhertu has already generated $5.4 billion in sales, and its total sales are forecasted to surpass $42 billion by 2028.

Telisotuzumab Vedotin (Teliso-V) by AbbVie

According to recent market research by ZoomRx, Teliso-V (telisotuzumab vedotin), an ADC developed by AbbVie, is predicted to be one of the most anticipated new oncology drugs for 2025. AbbVie released Phase II clinical trial data late last year, showing promising results for Teliso-V in the treatment of NSCLC.

Encouraged by these positive results, AbbVie plans to submit an application for accelerated approval of Teliso-V in the third quarter of this year, with a target launch in 2025.

Teliso-V is a first-in-class ADC that targets c-Met, a receptor tyrosine kinase overexpressed in many solid tumors, including NSCLC. Currently, there are no approved cancer therapies specifically targeting c-Met overexpression in NSCLC patients. The results from the single-arm Phase II LUMINOSITY trial, released last year, showed overall response rates of 35% and 23% in patients with high and moderate c-Met expression, respectively. Additionally, other key endpoints demonstrated significant clinical benefits, including median duration of response (9 months and 7.2 months) and median overall survival (14.6 months and 14.2 months).

Figure 1.  PFS and OS for patients with c-Met protein–overexpressing, nonsquamous EGFR-wildtype NSCLC receiving 1.9 mg/kg Teliso-V. [1]

Rina-S by Genmab

Genmab plays a pivotal role in the field of ADCs. In 2021, Genmab, in collaboration with Seagen, developed the ADC drug Tivdak, which became the first treatment for metastatic cervical cancer to receive accelerated approval. In April 2024, Tivdak  received full approval from the FDA. Data from key Phase III clinical trials showed that Tivdak significantly improved patient survival rates by 30% compared to chemotherapy.

To further strengthen and expand its leadership in the ADC field, Genmab made a strategic move by acquiring ProfoundBio for $1.8 billion  in 2024. This acquisition integrates ProfoundBio’s advanced ADC technology platform with Genmab’s proprietary antibody therapies, greatly enriching Genmab's development pipeline, which includes the ADC candidate Rina-S, currently in Phase II clinical trials.

Rina-S is a potential best-in-class, clinical-stage, FRα-targeted, Topo1 ADC for the treatment of ovarian cancer and other FRα-expressing solid tumors. In January 2024, the FDA granted Fast Track designation to Rina-S for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer.

Genmab highlights Rina-S’s innovative linker technology as a key advantage. This technology offers greater safety compared to direct competitors, such as Elahere, which carries a severe black box warning for eye toxicity. As a representative of second-generation ADCs, Rina-S features a cleavable hydrophilic linker design, and current data from clinical trials have shown no signs of eye toxicity, providing a strong foundation for its future clinical application.

Luveltamab Tazevibulin (luvelta, STRO-002) by Sutro Biopharma

Luveltamab tazevibulin, commonly known as luvelta or STRO-002, is an innovative ADC that targets the folate receptor alpha (FRα). It features a stable, cleavable linker and a 3-aminophenyl hemiasterlin payload (DAR=4), designed to induce cytotoxicity and immune cell death. Luvelta employs site-specific conjugation technology to effectively target ovarian cancer (OC) with broad FRα expression. The ongoing global Phase I trial, STRO-002-GM1, is focused on evaluating the efficacy and safety of luvelta in patients with recurrent OC, and researchers have recently provided updated data from the initial OC expansion cohort.

Figure 2. Structure of Luveltamab tazevibulin

Although Sutro Biopharma has not yet announced a specific timeline for submitting luvelta for regulatory approval, the potential impact of this drug is noteworthy. Once approved, luvelta will be specifically aimed at patients with ovarian cancer who express the FRα protein, a population expected to be more than twice the size of the group targeted by Elahere.

Beyond ovarian cancer, Sutro foresees significant potential for luvelta in treating NSCLC and other solid tumors. Sutro’s CEO, Bill Newell, has emphasized that the company takes a distinct approach to developing ADCs, focusing on the design of “homogeneous molecules.” This innovative strategy aims to enhance drug efficacy, benefit a larger patient population, and significantly reduce side effects.

In addition to its work on luvelta, Sutro has entered into a $900 million collaboration with Ipsen to co-develop ADC projects targeting solid tumors. The company has also partnered with Astellas Pharma to accelerate the development of immunostimulatory ADCs (iADCs). This cutting-edge technology has the potential to deliver two different drugs simultaneously to a tumor target, not only directly destroying cancer cells but also triggering a localized immune response against the patient’s specific tumor cells, achieving a dual therapeutic effect.

TUB-040 & TUB-030 by Tubulis

Tubulis focuses on developing next-generation payload technologies as a core part of its strategy for creating ADCs. This year, the company successfully completed a $138.8 million Series B2 financing round, which will be used to advance a range of innovative ADC drugs. These drugs are designed with customized targeting molecules and potent payloads, tailored for various indications. Among them, the key candidates TUB-040 and TUB-030 have completed clinical proof-of-concept studies, showing great promise.

TUB-040 targets the Napi2b tumor antigen, which is clearly expressed in ovarian cancer and lung adenocarcinoma, while TUB-030 is designed to target the 5T4 antigen, commonly overexpressed in multiple solid tumors. Tubulis has initiated Phase 1/2a clinical trials for TUB-040, focusing on ovarian cancer and lung adenocarcinoma. These trials include dose escalation and dose optimization phases, aimed at identifying the optimal treatment regimen.

Figure 3. Linker of TBU-040, source: Tubulis

TUB-040 is composed of an IgG1 antibody that specifically recognizes Napi2b and is linked to the topoisomerase I inhibitor Exatecan using Tubulis' proprietary P5 conjugation technology. This results in a uniform drug-to-antibody ratio (DAR) of 8. The P5 conjugation technology employs a novel cysteine-selective chemical reaction, optimizing the ADC's cleavage process and selective payload release, thereby enhancing therapeutic efficacy while reducing off-target toxicity. Preclinical pharmacokinetic studies have confirmed that TUB-040 effectively delivers its payload precisely to the tumor site, minimizing damage to healthy tissues.

Notably, TUB-040 has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA), signifying its significant progress in the treatment of ovarian cancer and lung adenocarcinoma. This designation could accelerate its development and help bring this promising treatment to patients sooner.

The Rise of ADCs

The field of ADCs is currently experiencing a golden era, with rapid advancements in drug development and market expansion leading to a vibrant landscape where numerous new drugs are emerging.

In recent years, ADCs have played a pivotal role in the wave of mergers and acquisitions in the pharmaceutical industry. Notably, 2023 saw several high-profile deals that highlighted the immense potential of ADCs. Pfizer acquired Seagen for an astonishing $43 billion, signaling the significant promise of this field. Similarly, AbbVie made a bold move by investing over $10 billion in ImmunoGen, a pioneer in ADC development. Merck also secured global rights to three ADC products from Daiichi Sankyo by paying a massive $22 billion in upfront fees, including an initial $4 billion payment. As 2024 began, Johnson & Johnson fully acquired Ambrx Pharma for $2 billion in cash, while Roche entered into a major licensing agreement with MediLink Therapeutics. These transactions have further accelerated the rapid growth of the ADC market.

Enhertu, a leading ADC drug, is expected to achieve an impressive peak sales figure of $10 billion, setting a benchmark for the entire industry. By 2028, the total sales of the ADC market are projected to approach $30 billion. At that point, ADCs will not only remain a key asset in the merger and acquisition market but will also establish themselves as essential drugs in cancer treatment, becoming a critical component of anti-cancer therapies.

Huateng Pharma is dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC discovery and development projects.

References:

[1] 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). AbbVie Press Release. 29. 11. 2023.

[2] Taylor, N. P. AbbVie ADC tops oncologist ranking of most exciting cancer candidates. Fierce Pharma. 26. 07. 2024.

[3] Liu, A. Enhertu stalls as AstraZeneca, Daiichi navigate 'harder yards' for ADC star. Fiercepharma. 25. 07. 2024.

[4] Tubulis Receives FDA Fast Track Designation for Antibody-Drug Conjugate Candidate TUB-040 in Platinum-resistant Ovarian Cancer. Tubulis Press Release. 27. 06. 2024.

[5] Tubulis Doses First Patient in Phase I/IIa Trial Investigating ADC Candidate TUB-040 in Ovarian Cancer and Lung Adenocarcinoma. Tubulis Press Release. 20. 06. 2024.

[6] Parrish, M. Up-and-comers look for an edge in the bustling ADC field. Pharma Voice. 28. 06. 2024.

[7] Horinouchi, H. et al. Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC). 2024. 00:1-12. https://doi.org/10.1200/JCO.24.00720

[8] Evaluating Antibody Drug Conjugates. Evaluate Pharma. Retrieved on 05. 08. 2024.

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