ROR1 in Focus as a target for ADC-based treatments: Recent Developments and Industry Challenges – Part III

Ipsen has recently expanded its portfolio with the acquisition of STRO-003, a preclinical ROR1-targeting antibody-drug conjugate (ADC), and a new partnership with Marengo Therapeutics. Meanwhile, Immunome and Lyell Immunopharma are progressing with their ROR1 programs. However, recent setbacks for Caribou Biosciences and Oncternal Therapeutics underscore the ongoing challenges with this potential ADC target. As the industry pushes forward, these developments illustrate both the potential and the hurdles of targeting ROR1 in cancer therapies.

Ipsen Expands Portfolio with ROR1 Candidate and Strategic Partnerships

Ipsen has been actively expanding its portfolio recently. In early April, the company secured exclusive global rights to a preclinical ROR1-targeting candidate from Sutro Biopharma Inc., in a deal valued at up to $900 million. This candidate, STRO-003, is the first ADC to join Ipsen’s portfolio. It leverages Sutro’s site-specific technology to create a highly stable conjugate combined with exatecan payloads. Exatecan, a topoisomerase I inhibitor used for cancer treatment, is attached through a stable beta-glucuronide chemical linker. This linker minimizes the payload’s exposure to non-tumor tissues. According to both companies, the drug has demonstrated preclinical efficacy in solid tumors and hematological malignancies, potentially offering a differentiated safety profile.

ROR1, or receptor tyrosine kinase-like orphan receptor 1, is a cell surface protein involved in embryonic development but aberrantly expressed in various cancers. Initially important for cell signaling during development, ROR1 reactivates in malignancies such as breast cancer and leukemia, making it an appealing target for cancer therapies.

Researchers are focusing on ROR1 due to its potential as a therapeutic target. They are developing treatments that specifically target and inhibit ROR1 in cancer cells. This includes using ADCs that combine antibodies with cytotoxic drugs to selectively attack cancer cells expressing ROR1. Thus, while ROR1 itself is not an ADC, it is becoming a key target for ADC-based therapies aimed at improving treatment outcomes for patients with ROR1-expressing tumors.

ROR1 Landscape’s Ongoing Developments and Challenges

Several companies remain active in the ROR1 field. Immunome Inc., secured a $310 million exclusive license agreement with Zentalis Pharmaceuticals Inc. for the preclinical ROR1 ADC ZPC-21 in January. Immunome is also advancing its internal ROR1 ADC, IM-1021, with an IND submission planned for the first quarter of 2025. Additionally, Lyell Immunopharma Inc. is progressing its ROR1-targeted CAR T cell therapy, LYL-797, which is currently in Phase I trials for triple-negative breast cancer, non-small-cell lung cancer, and other solid tumors.

However, the ROR1 landscape has encountered notable challenges recently. Caribou Biosciences Inc., was developing CB-020, an induced pluripotent stem cell (iPSC)-derived allogeneic CAR-NK cell therapy for solid tumors. However, the company announced that it is pausing development as part of a portfolio prioritization strategy.

Further, Oncternal Therapeutics Inc. faced setbacks with its ROR1 inhibitor, zilovertamab. This drug, which had been studied in combination with ibrutinib (Imbruvica) in a Phase I/II trial for mantle cell lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, saw its studies halted in 2023. The decision came as a result of shifting dynamics in the commercial landscape for Bruton’s tyrosine kinase inhibitors.

Despite this. Oncternal continues to advance its ROR1-targeting candidate, ONCT-808. This drug showed promising results in a Phase I trial last December, with a complete metabolic response in two patients and a partial response in a third. However, one patient experienced severe adverse effects, including symptoms consistent with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which led to their death.

ROR1 as a Target for Cancer Therapies: Industry Advances Despite Setbacks and Challenges

Essentially, ROR1 is a cell signaling receptor that is over-expressed in various solid and liquid tumors, driving cancer growth, survival, and metastasis. It preferentially appears on tumor cells rather than normal cells. Research suggests that ROR1 mediates resistance to chemotherapy, promotes epithelial-mesenchymal transition, and enhances stem-like properties in tumor-initiating cells. Consequently, it has emerged as a significant target for the ADC market in developing new cancer therapies.

Ipsen’s acquisition of STRO-003 and its expanded partnership with Marengo Therapeutics underscore its strategic focus on ROR1-targeting therapies. Meanwhile, Immunome and Lyell Immunopharma continue to advance their ROR1 programs. In contrast, recent setbacks for Caribou Biosciences and Oncternal Therapeutics highlight the challenges faced in the ROR1 field, emphasizing the need for continued innovation and adaptation.

Author

Bernice Lottering