ADC Development Services Targeting Ephrin A4

Ovarian cancer and triple-negative breast cancer (TNBC) each comprise heterogeneous tumors, for which current therapies have little clinical benefit. New therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. With years of expertise in antibody drug conjugate (ADC) research and development, Creative Biolabs is highly qualified in process development and manufacturing of new ADCs with high potency from preclinical to commercial. Customized anti-EphA4 ADC development services as well as the off-the-shelf Anti- Ephrin A4 ADC are now available for our worldwide customers.

Introduction of Ephrin A4

Ephrin receptors can be classified into two subgroups (EphA and EphB) based on the structure of their extracellular domains and ligand-binding affinity. Both EphA and EphB are overexpressed on tumors and have been associated with progression and metastasis in several tumor types including breast, lung and pancreatic cancer. Ephrin A4, a member of the EphA receptors, has been demonstrated to be elevated in various human cancers and involved in the tumor progression. EphA4 can be activated by both A- and B-class ephrin ligands. EphA4 plays a vital role in a variety of cell-cell interactions in cancer biology as well as in the pathogenesis of several neurological disorders. Pharmacological blocking of EphA4 has been suggested to be a therapeutic strategy for these disorders. In addition, profiling of a series of patient-derived xenograft (PDX) models revealed elevated expression of EphA4 on TNBC tumors relative to that on normal adjacent breast tissue and other breast cancer subtypes.

Fig.1 Basic Eph receptor structure and signaling pathways. (Lamb, 2019)

Anti-Ephrin A4 ADC in Breast Cancer and Ovarian Cancer

TNBC and ovarian cancer each comprise heterogeneous tumors and current therapies have little clinical benefit for those two cancers. Ephrin A4 is broadly overexpressed in TNBC as well as ovarian cancer. To overcome the general obstacles to effectively targeting Ephrin ligands, an ADC was generated to deliver the potent DNA-damaging cytotoxic agent, specifically to Ephrin A4-expressing cells.

PF-06647263, with an average drug to antibody ratio (DAR) of 4.6, is an anti-EphA4 ADC in which caliacheamicin is conjugated to a humanized IgG1 anti-Ephrin A4 mAb through a two-stage linker system to mAb lysines. PF-06647263 was evaluated in breast PDX models and demonstrated to reduce TIC frequency and induce sustained tumor regressions in vivo in TNBC and ovarian cancer PDX tumor models.

Fig.2 Structure of SAR566658. (Trail, 2018)

What Can We Do for You?

Ephrin A4 is a prospective therapeutic target for breast cancer and ovarian cancer. Various ADC products comprising humanized anti-Ephrin A4 mAb conjugated to different toxins have been developed. Creative Biolabs offers tailor made services providing  a full package (chemistry and bioconjugation), or as stand-alone activities (payload or conjugation). Our ADC development services include but not limited to:

• Process development and manufacture of the cytotoxic drug-linker payload based on our DrugLnk™ Custom Synthesis platform
• Bioconjugation and process development for the production of the antibody-drug conjugates based on our ADC Antibody Screening, Antibody Design and Conjugation as well as antibody engineering techniques
• Analytical method development and validation, ADC in vitro Analysis and ADC in vivo Analysis

Our company can fully support all the stages of the ADC pipeline, starting from antibody discovery and linker-payload design to  ADC GMP manufacturing. Please feel free to contact us for more information.

References

1. Lamb, T. J.; Darling, T. K. Emerging roles for Eph receptors and ephrin ligands in immunity. Frontiers in immunology. 2019, 10: 1473.
2. Trail, P. A,; et al. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacology & therapeutics. 2018, 181: 126-142.

For Research Use Only. NOT FOR CLINICAL USE.