Two-pronged antibodies draw immune killers directly to cancer cells

Our immune system’s arsenal of defenses usually protects us from cancer. But sometimes, cancer cells overwhelm or evade this elaborate defense system.

Scientists at The Scripps Research Institute in Florida say they have engineered a new type of anticancer antibody, one intended to enhance nature’s cancer-fighting strategies by attracting killer T cells directly to cancer cells covered with a distinctive protein.

Dubbed T-cell-engaging bispecific antibodies, these cancer combatants attack malignant cells but reportedly leave healthy cells untouched. That’s due to their selective targeting system, which zeroes in on a protein found on the surface of several types of cancer cells called ROR1, and also due to their ability to bind with T cells.

“Once the T cells are recruited and activated, they release cytotoxic molecules that penetrate the target cells and kill them,” says Christoph Rader, Ph.D., associate professor at the institute. “Natural antibodies can’t do this. You have to engineer them in a bispecific fashion to do this.”

The scientists’ work is described in the article “Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1,” which appears online in Proceedings of the National Academy of Sciences (PNAS).

“T cell-engaging bispecific antibodies (biAbs) present a promising strategy for cancer immunotherapy, and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T cell-engaging biAbs targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 × CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory t_1/2 and diminished systemic T cell activation. A diverse panel of ROR1-targeting scFv derived from immune and naïve rabbit antibody repertoires was compared in this bispecific format for target-dependent T cell recruitment and activation,” write the investigators.

“An ROR1-targeting scFv with a membrane-proximal epitope, R11, revealed potent and selective antitumor activity in vitro, in vivo, and ex vivo and emerged as a prime candidate for further preclinical and clinical studies. To elucidate the precise location and engagement of this membrane-proximal epitope, which is conserved between human and mouse ROR1, the 3D structure of scFv R11 in complex with the kringle domain of ROR1 was determined by X-ray crystallography at 1.6-Å resolution.”

Dr. Rader is particularly interested in applying his bispecific antibodies to a type of breast cancer with fewer treatment options, HER2-negative breast cancer.

“If you look at ROR1 expression in breast cancer, you see that the patients who are HER2 negative are often ROR1 positive,” Dr. Rader says. “These breast cancer patients might benefit.”

ROR1 is an excellent target for a smart cancer-fighting system, according to Dr. Rader, because it is seen only in mature cells that are malignant. He first discovered ROR1’s activity in leukemia a decade ago while working at the National Cancer Institute.

“ROR1 is expressed during embryogenesis, and then it is tightly downregulated after birth. It later reappears in both blood cancers and solid malignancies,” explains Dr. Rader, who adds that it has been found on malignant cells including lung, breast, ovarian and blood-based cancers.

“One of the most unique aspects of this bispecific antibody is that it can work in so many different cancer indications,” he continues.