Development of Biparatopic FRα-targeted Bispecific ADCs

Promising targeted treatments utilizing bispecific antibody, antibody-drug conjugates (ADC) and immunotherapy strategies in oncology have reignited interest in the tumor-associated antigen folate receptor alpha (FRα). As a leader in the ADC development field, Creative Biolabs has put a lot of energy and time into bispecific ADC research. Dual targeting of a protein by biparatopic ADC can enhance toxin delivery into tumor cells. With years of experience in the field of antibody discovery and conjugation, Creative Biolabs now provides biparatopic FRα-targeted bispecific ADCs development as well as characterization services for our global clients.

Introduction of FRα

FRα, also known as FOLR1 or folate binding protein (FBP), is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with a high affinity for binding and coordinating transport of the active form of folate, 5-methyltetrahydrofolate (5-MTF). FRα has been reported to be overexpressed in solid tumors such as lung, ovarian, and breast carcinomas. However, the distribution of FRα in normal human tissues is restricted to low level expression in the apical surfaces of some organs such as the kidney, lung, and choroid plexus. Its overexpression in tumors and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target.

Fig.1 A model depicting FRα-mediated internalization of folates and regulation of cancer signaling. (Cheung, 2016)

FRα-targeted Approaches

A range of FRα-targeting approaches, including small molecules, T-cell therapies, monoclonal antibodies (mAbs), and ADCs have been developed for clinical application for both imaging and therapeutic purposes. For instance, Farletuzumab (MORab003) is a fully humanized IgG1 antibody specific for FRα, exerting antitumor activity against FRα-expressing tumor cells through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), sustained tumor cell autophagy, and inhibition of Lyn kinase substrate phosphorylation.

Fig.2 Clinical applications of FRα-targeting agents in the diagnosis and treatment of cancer. (Scaranti, 2020)

Mirvetuximab soravtansine (IMGN853) is an ADC consisting of a cytotoxic agent, the maytansinoid DM4, conjugated to a humanized anti-FRα monoclonal antibody via the disulfide-containing hydrophilic linker sulfo-SPDB. Preclinical studies have demonstrated in vitro and in vivo anti-tumor activity of this ADC in models of ovarian cancer and NSCLC. MORAb-202, comprising a self-emolative Val-Cit linker and a drug-to-antibody ratio (DAR) of 4, displayed optimal biophysical properties, potent cytotoxicity across several FRα-positive cell lines, and induced a robust antitumor response in mouse models of FRα-positive human cancers.

Fig.3 Structure of IMGN853 and MORAb-202.

What Can We Do for You?

The biparatopic antibody promotes receptor internalization and lysosomal degradation, it should serve as an effective vehicle to deliver toxins into the target cells in the form of ADC. At present, Creative Biolabs is capable of developing biparatopic antibodies to distinct, non-overlapping epitopes that serve as reagents for biparatopic FRα-targeted bispecific ADC development. The best biparatopic ADC construction services against the FRα are available upon request, and we will apply our first-hand expertise to your distinct project requirements. If you are interested in our services, please do not hesitate to contact us for more details.

References

1. Cheung, A.; et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016, 7(32): 52553.
2. Scaranti, M.; et al. Exploiting the folate receptor α in oncology. Nature Reviews Clinical Oncology. 2020: 1-11.

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