Topo-1 and FRα: Key Focus Areas and Major Collaborations in ADC Research – Part I

In recent months, the antibody-drug conjugate (ADC) field has witnessed significant advancements and several strategic moves, revealing its dynamic growth. Notable developments include Foreseen Biotechnology Co. Ltd.’s lucrative licensing agreement with Ipsen SA for their ADC FS-001, targeting a novel tumor-associated antigen with promising preclinical efficacy. Additionally, significant progress in topoisomerase 1 and FRα-targeted treatments has further accelerated the ADC agenda. This dynamic development highlights the sector’s rapid evolution and increasing impact on cancer therapy.

Global Collaboration to Push the ADC Agenda

In one of the latest moves within the lively ADC space, Foreseen Biotechnology Co. Ltd. has secured a global licensing agreement with Ipsen SA worth up to $1.03 billion for their ADC, FS-001. The drug targets a novel tumor-associated antigen, prevalent in many solid tumors, and plays a crucial role in tumor proliferation and metastasis. FS-001 features a linker coupled to a potent topoisomerase 1 (topo-1) inhibitor, with preclinical efficacy demonstrated in multidrug-resistant cancer models. 

Foreseen, though relatively under the radar with its website currently under maintenance, describes itself as a pioneering biotechnology company using a high-throughput integrated translational proteomics platform powered by AI-based data analytics to develop diagnostics and drugs. Consequently, Foreseen will receive an undisclosed up-front payment, milestone rewards, and tiered royalties on sales. Notably, Ipsen will manage phase I preparations, including the Investigational New Drug (IND) application, and oversee all subsequent clinical development, manufacturing, and commercialization.

Topo-1 inhibitors, a class of chemotherapy drugs, disrupt DNA replication by targeting the topo-1 enzyme. This enzyme relieves DNA supercoiling during replication by creating temporary single-strand breaks. Topo-1 inhibitors, however, block this relaxation, leading to persistent DNA damage and ultimately causing cancer cell death. Drugs like irinotecan and topotecan exemplify this approach, offering an alternative mechanism to ADCs by focusing on disrupting DNA repair processes.

In contrast, topo-1-targeted ADCs combine an antibody’s targeting abilities with the cytotoxic effects of a topo-1 inhibitor. The antibody specifically binds to cancer cells with high topo-1 expression. After internalization, the ADC releases the cytotoxic drug, which then interferes with topo-1 activity, causing DNA damage and cell death. As a result, topo-1 ADCs effectively deliver potent topo-1 inhibitors directly to cancer cells, enhancing treatment efficacy while reducing off-target effects.

Topo-1 and FRα Hot on the ADC Research Radar

Topo-1, the target central to Foreseen’s recent deal, has also been involved in other notable takeovers. In October 2023, Eli Lilly and Co. of Indianapolis acquired Lyon-based Mablink Bioscience SAS. Mablink’s hydrophilic drug-linker technology allows for the creation of homogeneous, plasma-stable, next-generation ADCs. Funded by a seed round led by Elaia Partners in 2021, Mablink’s acquisition terms were not disclosed. Furthermore, around the time Ipsen announced its deal with Sutro, Genmab A/S revealed its $1.8 billion cash acquisition of Seattle-based ADC specialist Profoundbio Inc. This transaction stands as the largest to date for the Copenhagen-based biopharma company.

Here, the acquisition brought in a clinical-stage pipeline, headed by the phase II-stage rinatabart sesutecan (Rina-S), an FRα-targeted ADC for ovarian cancer and other solid tumors. Additionally, it included preclinical candidates and Profoundbio’s ADC technologies. These technologies featured a novel hydrophilic linker-drug platform, enabling the use of hydrophobic payloads at drug-to-antibody ratios (DARs) up to eight or higher. Rina-S received FDA fast track designation for advanced ovarian cancer. If all goes as expected, Genmab predicts potential approval by 2027 and envisions the therapy achieving “blockbuster peak sales potential.”

More comprehensively, the FRα-targeted ADC is a specialized cancer therapy designed to deliver cytotoxic drugs directly to cancer cells expressing folate receptor alpha (FRα). This ADC comprises an antibody that specifically binds to FRα, coupled with a potent cytotoxic drug. Upon binding, the ADC is internalized by the cancer cell, where the cytotoxic agent is released, leading to targeted cell death. Consequently, FRα-targeted ADCs are particularly effective in treating cancers like ovarian cancer that exhibit high levels of FRα expression.

ADC Forging a New Path in Cancer Therapeutics and More

The surge in ADC advancements highlights a transformative phase in biotech. Foreseen Biotechnology’s $1.03 billion licensing deal with Ipsen SA, featuring the topo-1 inhibitor FS-001, underscores the industry’s focus on innovative cancer therapies. Additionally, Eli Lilly’s acquisition of Mablink Bioscience SAS and Genmab’s $1.8 billion purchase of Profoundbio Inc., which includes the FRα-targeted ADC Rina-S, reflect broader trends in next-generation ADC development. Consequently, these strategic moves and technological advancements signal a significant shift towards more targeted and effective cancer treatments, promising to reshape the oncology landscape and industry.

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Author

Bernice Lottering