Phase 1 Trial for ITC-6146RO, Antibody-Drug Conjugate Targeting B7-H3

ITC-6146RO is an experimental cancer drug belonging to the class of antibody–drug conjugates, or ADCs. It received IND Approval from Korean Ministry of Food and Drug Safety (Following U.S. FDA) to start a first‑in‑human Phase 1 trial in people with advanced or metastatic solid tumors who no longer respond to standard therapies.

It has been designed to attack tumors that display a surface protein called B7-H3, which is found at high levels in several aggressive cancers such as metastatic castration‑resistant prostate cancer, non‑small cell lung cancer, and triple‑negative breast cancer. The goal is to bring a very powerful chemotherapy payload directly to cancer cells while sparing as much healthy tissue as possible, widening the therapeutic window compared with classical chemotherapy.​

The structure of ITC-6146RO has three main components: an antibody that recognizes B7‑H3, a chemical linker called OHPAS, and a duocarmycin‑based payload, which is an extremely potent DNA‑damaging agent. After intravenous administration, the antibody part binds to B7‑H3 on the tumor cell surface and is pulled into the cell through a process called endocytosis, ending up in acidic compartments called lysosomes. Inside these lysosomes, the OHPAS linker is cleaved and the duocarmycin derivative is released, migrates to the nucleus, alkylates DNA, disrupts cell division in S phase, and ultimately causes tumor cell death. This “guided missile” architecture is typical of modern ADCs, but ITC‑6146RO adds platform innovations aimed at greater stability in blood and more selective activation inside tumors.​

The OHPAS linker has been engineered to be very stable while the drug circulates, so that the toxic payload is not shed prematurely into the bloodstream, which would increase systemic toxicity. It is designed to break efficiently only under specific conditions in the tumor cell environment, such as enzymatic activity and acidic pH in lysosomes, ensuring that most of the duocarmycin is released where it is needed. On top of this, payload modification technology is used to temporarily “mask” chemical features of the toxin that would otherwise lead to uptake in normal cells, with the intent of reducing off‑target damage and improving the therapeutic index. Together, these design choices aim to combine high potency with acceptable tolerability, a central challenge for all ADCs.​

B7‑H3 itself is an attractive but still unproven cancer target at the clinical level. It is overexpressed in many solid tumors and usually low in normal tissues, which helps selectivity. Biologically, B7‑H3 appears to play a dual role: it can suppress immune responses by inhibiting T cells and natural killer cells, and it can also act directly within tumor cells to promote growth, blood vessel formation, metastasis, and resistance to treatment through pathways such as PI3K/AKT and JAK/STAT. Because of this, drugs like ITC‑6146RO could theoretically work both by directly killing tumor cells and by indirectly remodeling a hostile tumor microenvironment, especially if later combined with other immunotherapies.​

In B7‑H3‑positive lung and breast cancer models, it showed strong killing of tumor cells, induced DNA damage and S‑phase arrest, and produced sustained tumor regressions in xenograft and patient‑derived xenograft models. Toxicology data in these studies suggested good stability in circulation and limited damage to non‑tumor immune cells compared with more traditional ADC designs, supporting further development.

Because no B7‑H3‑targeting therapies have yet been approved, data from this and similar trials will be crucial to determine whether B7‑H3 ADCs, and ITC‑6146RO in particular, can deliver meaningful clinical benefit with manageable toxicity in heavily pretreated patients.