Anti-HER2 Antibody Development

In clinical diagnosis, prior to treatment, patients are examined via a series of clinical diagnostic tests. In breast cancer, detection of breast cancer-associated biomarkers is of great significance and human epidermal growth factor receptor 2 (HER2) is particularly important. Besides the expertise in high-resolution imagery, molecular tracking, Creative Biolabs is also dedicated to the areas of antibody design and engineering. Empowered by our advanced and comprehensive technical platforms, Creative Biolabs now provides customized antibody development services against HER2 with different strategies.

HER2 Ectodomain Shedding

HER2 is a 185 KDa transmembrane protein encoded by the HER2 gene and over-expressed in approximately 15% of invasive breast cancers. HER2 belongs to the human epidermal growth factor (EGF) receptor family, which comprises HER2, HER3, HER4, and EGFR. Different from the other members of the family, HER2 does not bind any growth factors and has no known ligand, thereby it is activated through homodimerization or heterodimerization with another member of the HER family, or by proteolytic cleavage of its extracellular domain (ECD). The ECD of HER2 is released from the surface of tumor cells into the blood by a proteolytic shedding process mainly mediated by ADAM (a disintegrin and metalloproteinase) 10. This proteolytic shedding generates a constitutively active truncated receptor p95^HER2 in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Soluble HER2 (sHER2 ECD) has been considered as a useful biomarker for cancer recurrence and monitoring disease status in breast cancers that over-express HER2.

Fig.1 The domain structure of HER2. (Perrier, 2018)

Antibody Strategies against HER2

Trastuzumab was the first HER2-targeted therapy approved by the FDA in 1998 for the treatment of metastatic breast cancers that over-express HER2. However, cells acquire resistance to trastuzumab and pertuzumab by shedding the HER2 ECD, which contains the epitopes recognized by these two monoclonal antibodies (mAbs), into serum where it can bind to and neutralize the antibodies. Therefore, clinically, combination therapies of trastuzumab and other anti-HER2 agents are commonly conducted to optimize their therapeutic efficacy.

In another way, Creative Biolabs could provide completely new therapy strategies which focus on the ECD shedding to overcome trastuzumab resistance in HER2+ tumors. Since the exact sites of ECD shedding are clear and there remains a constitutively active, truncated, membrane-bound receptor CFTs p95, antibodies could be specially developed to mask the cleavage sites to prevent HER2 shedding, then further conjugated with drugs to form an antibody-drug complex (ADC) to kill tumor cells that over-express HER2. Now that the shedding process on HER2 is suppressed, antibodies could be also combined with existing antibodies and derivatives such as Ado-trastuzumab emtansine (T-DM1) to exert their respective functions.

Fig.2 Structure of T-DM1 and mechanisms of action. (Lambert, 2014)

Features

• Personalized: Custom-built anti-HER2 antibody development services to meet our customers' requirements.
• Comprehensive: Full-scale antibody development and antibody conjugation platform.
• Cost-effective: Competitive price with the best quality.
• Innovative strategies: Different antibody development strategies against various targets according to their shedding mechanism.

Equipped with state-of-the-art research and manufacturing facilities, Creative Biolabs has gained significant knowledge and rich experience in antibody-related services. We are more than happy to share our experience and help our customers in antibody development. Please contact us for more information and a detailed quote.

References

1. Perrier, A.; et al. The extracellular domain of her2 in serum as a biomarker of breast cancer. Laboratory investigation; a journal of technical methods and pathology. 2018, 98(6), 696.
2. Lambert, J. M.; Chari, R. V. Ado-trastuzumab emtansine (t-dm1): an antibody-drug conjugate (adc) for her2-positive breast cancer. Journal of Medicinal Chemistry. 2014, 57(16), 6949.

For Research Use Only. NOT FOR CLINICAL USE.