B7-H4 Is Validated as a Target for ADCs in High-Grade Serous Ovarian Carcinoma

As B7-H4 is overexpressed in breast and ovarian cancers, investigators examined its expression in high-grade serous ovarian carcinoma (HGSOC) tumors at diagnosis and following resistance to platinum or PARP inhibitor treatment, according to Sarah B. Gitto, PhD.

Gitto presented data at the 2023 AACR Annual Meeting, which demonstrated the target’s expression is maintained even when cancer becomes drug resistant.1 “We evaluated for donors with multiple metastatic lesions and saw that the target B7-H4 is expressed across all the lesions that we analyzed,” Gitto said. “Potentially, this target could be used in the recurrent setting after our standard-of-care [SOC] therapies, [using] a drug that [engineered to] target [expression on] all lesions in the body, hopefully providing better opportunity for cures.”

The study authors wrote that at diagnosis, “B7-H4 was over-expressed in 92% of [high-grade serous carcinoma] HGSOC tumors at diagnosis (n = 12), [and expression] persisted in recurrent matched samples after platinum treatment and was expressed at similar levels at multiple metastatic sites after acquired multidrug resistance (n = 4 donors).”¹

To analyze B7-H4 expression after treatment, researcher evaluated a panel of 10 B7-H4 expressing ovarian and breast cancer cell lines following treatment with a novel B7-H4–directed antibody-drug conjugate (ADC), designed with the pyrrolobenzodiazepine-dimer payload tesirine. The ADC resulted in target-specific growth inhibition with a median of 48.3 pM (IC50 6.18-273.9 pM). In models of high-grade serous ovarian carcinomas that had resistance following PARP inhibitor and platinum-based therapy, sustained antitumor activity was seen with continuous dosing.¹

Gitto noted that the ADC used in this research will not be moving forward for clinical use because of off-target toxicities. “This work validated B7-H4 as a target that is present throughout the disease progression even in the resistant setting and validated this approach and provided rationale for using next generation ADCs that are currently being studied in the clinic.”¹

In an interview with OncLive^®, Gitto, instructor A of pathology and laboratory medicine at the University of Pennsylvania, discussed the process of investigating the B7-H4 as a viable target for drug development in treatment-resistant ovarian cancer.

OncLive^®: What was the rationale for investigating B7-H4 expression?

Gitto: It was very exciting that we were able to validate [that], B7-H4 is overexpressed in a variety of solid tumors including ovarian cancer and breast cancer. Approximately 70% of ovarian cancers have this protein expressed on the cell surface [and] because it’s on the cell surface we’re able to target it with different therapies.

[We looked] at an ADC, a compound that has an antibody that targets a protein, in this case [we examined] B7-H4. It has a chemotherapy or a cytotoxic agent that’s attached to it, [which can be internalized] after binding specifically to the target, killing the tumor cell. So, instead of having a systemic therapy that causes a lot of toxicities like with chemotherapy, we can direct that cytotoxic effect to the tumors.

What methods were used throughout your investigation?

We validated the activity of the drug in vitro using a variety of methods [including] survival assays, colony formation assays, flow cytometry to look at cell cycle arrest, and DNA damage caused by the agent. We also validated the activity of the drug in vivo using multiple patient-derived xenograft models—we had 32 patient-derived xenograft models of both breast and ovarian cancer with a variety of expression levels of the B7-H4 target to validate that the therapy was actionable.

We also validated expression patterns in a variety of donor tumors, and [although] it’s well established that B7-H4 is expressed in both ovarian and breast, there’s a long list of solid tumors that express it. What was unknown was how [or if] SOC chemotherapy or PARP inhibitors, which are common [treatments used for patients with] ovarian cancer, affect the protein expression.

In clinical trials, you [can] test new therapies [for] tumors that are resistant to SOC therapies. The target needs to be expressed in the resistant setting because that’s who’s going to be getting the therapies [and] those are the patients [for whom] we need to try to find cures.

Please discuss the research you presented at the 2023 AACR meeting.

This research was the first to show that the expression of B7-H4 is maintained after SOC therapy and we tested that using donor match samples at baseline or at diagnosis and then again in the recurrent setting or after they had [treatment with] chemotherapy or PARP inhibitors. We found that the majority of tumors, if they had expression originally, usually had expression after they became resistant.

We also looked at various metastatic lesions. There is a program at the University of Pennsylvania [where we] have a tumor bank [the Penn Ovarian Cancer Research Center Tumor BioTrust Collection], which has over 1500 donor tumors collected from women who have gynecological cancers. We used that bank, but we also have a rapid autopsy program [where] at the end of life we’re able to collect tissues at the time of passing, to understand the variability of tumors and various metastatic lesions.

How can the discovery of additional targets affect the treatment paradigm?

[With] ADCs, FRα is a target that’s present in approximately 70% of ovarian cancers and that has just been clinically approved for the treatment of ovarian cancer.² The space and the field are moving forward regarding approvals for these types of therapies and that also is really exciting. There’s a lot of hope for moving forward [with these] treatment options for patients with ovarian cancer and I’m looking forward to helping drive new discoveries that hopefully will make a difference for patients.

I would also like to thank the donors and the patients who were able to provide their tumors to help us better study and find these new cures and new approaches, it really makes a difference.

References

1. Gitto SB, Whicker M, Davies G, et al. A B7-H4 targeting antibody-drug conjugate shows anti-tumor activity in PARPi and platinum resistant cancers with B7-H4 expression. Cancer Res. 2023;83 (suppl7):1133. doi:10.1158/1538-7445.AM2023-1133
2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. FDA. November 14, 2023. Accessed April 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications