Targeted cancer therapies offer a precise approach in oncology, designed to attack cancer cells while minimizing harm to healthy tissues. ROR1 ADC is a novel strategy within this field, delivering potent anti-cancer agents directly to malignant cells.
What is ROR1 ADC?
ROR1 ADC is an Antibody-Drug Conjugate (ADC) that targets Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). ROR1 is a protein found on the surface of many cancer cells, including those in various blood cancers and solid tumors. It is typically absent or present at very low levels on healthy adult cells, making it an appealing target for cancer therapies.
An Antibody-Drug Conjugate (ADC) is a sophisticated type of targeted therapy that combines three main components: a monoclonal antibody, a potent chemotherapy drug (payload), and a linker connecting the two. The antibody acts as a homing device, designed to recognize and bind to specific proteins, or antigens, on the surface of cancer cells. The payload is a highly effective cytotoxic agent, too potent to be given systemically on its own due to severe side effects.
The linker serves as a stable bridge, keeping the payload attached to the antibody until it reaches its intended destination. A ROR1 ADC is specifically engineered to deliver its therapeutic payload to cancer cells that express the ROR1 protein. This design aims to concentrate the drug’s effect where it is needed most, thereby increasing efficacy and reducing systemic toxicity.
How ROR1 ADC Targets Cancer
The mechanism of ROR1 ADC action begins with its precise recognition and binding. The antibody component of the ROR1 ADC is designed to specifically identify and attach to ROR1 proteins located on the outer surface of cancer cells.
Following successful binding, the ROR1-ADC complex is then internalized, meaning it is taken inside the cancer cell. This internalization process typically involves the cell’s natural uptake mechanisms, where the ADC is enveloped and drawn into the cellular interior. Once inside the cancer cell, the environment changes, triggering the next crucial step.
Within the cancer cell, the linker that connects the antibody and the drug payload is cleaved, or broken apart. This cleavage can be facilitated by specific enzymes or conditions found predominantly inside the cancer cell, ensuring the payload is released in the correct location.
Upon release, the potent chemotherapy drug is now free to act within the cancer cell. This liberated drug then interferes with essential cellular processes, such as DNA replication or microtubule function, which are necessary for cell division and survival. By disrupting these processes, the released drug ultimately leads to the destruction of the cancer cell, while minimizing damage to healthy cells that do not express ROR1.
Cancers Where ROR1 ADC Shows Promise
ROR1 ADC holds promise across various cancer types where ROR1 expression is notably elevated, making it an attractive therapeutic target. This includes blood cancers like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), where ROR1 is frequently found on malignant cells. In CLL, ROR1 expression is tightly correlated with disease progression.
Beyond blood cancers, ROR1 ADC is also being investigated for several solid tumors. Triple-negative breast cancer (TNBC), a challenging subtype due to its lack of common therapeutic targets, frequently exhibits ROR1 expression. High ROR1 expression in breast cancer is associated with more aggressive disease progression.
Lung cancer, particularly lung adenocarcinoma, and ovarian cancer are other areas where ROR1 ADC shows potential. ROR1 has been implicated in promoting tumor cell survival and inhibiting apoptosis in lung cancer. ROR1 expression has also been noted in other malignancies such as colorectal, endometrial, gastric, melanoma, and pancreatic cancers.
The Journey of ROR1 ADC Through Development
ROR1 ADCs are progressing through various phases of clinical development, reflecting ongoing efforts to bring these targeted therapies to patients. Many ROR1-targeting ADCs are undergoing Phase 1 and Phase 2 clinical trials, designed to assess their safety, dosage, and effectiveness in human patients. For example, RB-164™ is in a Phase 1 clinical trial in the U.S., Australia, Europe, and China, evaluating its safety, efficacy, and pharmacokinetics in patients with ROR1-positive hematologic malignancies and advanced solid tumors.
Researchers are exploring ROR1 ADCs as standalone treatments and in combination with other established cancer therapies. For instance, zilovertamab vedotin, a ROR1-targeting ADC, is being studied in combination with R-CHP chemotherapy in a Phase 3 trial for diffuse large B-cell lymphoma (DLBCL). Another ADC, MK-2140, showed encouraging results in a Phase 1 study for advanced MCL and DLBCL, leading to a Phase 2 study for solid tumors, including breast and lung cancer.
Preliminary findings from these trials indicate promising activity, such as inducing cell cycle arrest and apoptosis in preclinical models, and achieving tumor growth inhibition in animal models. The development of next-generation ROR1 ADCs is also underway, aiming to refine these therapies and expand their therapeutic applications for a broader range of cancers.