Development of Biparatopic HER2-targeted Bispecific ADCs

Antibody-drug conjugates (ADCs) can deliver cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking, which has been regarded as an effective cancer therapy strategy. With years of experience in the field of antibody discovery and bioconjugation, Creative Biolabs represents one of the leaders in the field of small molecular synthesis, antibody engineering as well as ADC development. Currently, we provide a novel ADC development service, which is named biparatopic bispecific ADCs that target two different non-overlapping epitopes of HER2. We believe our services will effectively save the time and cost of your programs by taking advantage of our expertise and innovative technology platforms.

Introduction of HER2

HER2 (also known as receptor tyrosine-protein kinase erbB-2, CD340, proto-oncogene Neu or ERBB2), is a protein encoded by the ERBB2 gene located on the long arm of chromosome 17. HER2 is a member of the human epidermal growth factor receptor (EGFR) family that consists of three other receptors, epidermal growth factor receptor (HER1, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). HER2 is aberrantly overexpressed in certain malignancies such as breast and gastric cancer. It is overexpressed in around 20-30% of breast cancer tumors. HER2 is considered as an oncogenic driver in HER2 amplified cancers since it involves promoting tumorigenesis through multiple mechanisms. Dysregulated HER2 expression often results in an increased risk of recurrence and poorer prognosis in cancers. In HER2-positive malignancies, it can stimulate downstream RAS-RAF-ERK and PI3K-PTEN-AKT signaling to facilitate cancer cell proliferation. Thus, HER2 has become an important biomarker and therapeutic target in cancer diagnosis and targeted treatment such as the ADCs.

Schematic diagram of HER2 signaling pathways. Fig.1 Extracellular Domains of HER2 and Antibody Binding. (Damelin, 2018)

Biparatopic HER2-targeted Bispecific ADC

Following ado-trastuzumab emtansine (T-DM1), multiple novel HER2-targeted ADCs have been developed and shown the promise of improved potency and efficacy. At present, biparatopic HER2-targeted bispecific ADCs represent a new format in these ADCs. For example, a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 conjugated to a tubulysin-based microtubule inhibitor can induce significant HER2 receptor clustering and enhance robust internalization, lysosomal trafficking, and degradation. This biparatopic ADC demonstrates potent anti-tumor activity over T-DM1 in tumor models. Therefore, the biparatopic ADC is considered as a promising potential therapy for metastatic breast cancer. Besides, safety studies in non-human primates demonstrated that the biparatopic ADC is sufficient to enter clinical trials. To date, a phase I clinical trial to assess the safety and preliminary efficacy of the biparatopic ADC is underway in patients refractory to or ineligible for current HER2-targeted therapies.

Mechanism of action (MOA) of biparatopic HER2-targeted bispecific ADC. Fig.2 Mechanism of action (MOA) of biparatopic HER2-targeted bispecific ADC. (Li, 2016)

ZW49 is another anti-HER2 biparatopic ADC composed of an Azymetric anti-HER2 IgG1 linked to ZymeLink Auristatin via a protease cleavable linker. Preclinical study showed that ZW49 demonstrates significant lysosomal trafficking and superior internalization relative to the HER2-targeted monospecific ADC. Besides, this biparatopic ADC presents greater tolerability and exposure. These properties enable ZW49 to generate complete responses in HER2 low to high-expressing PDX models at exposures tolerated in non-human primates. So far, ZW49 has been evaluated in Phase 1 clinical trial since initiated in 2019.

What Can We Do for You?

ADCs presently are developed rapidly due to the powerful platform and optimized conjugation strategies, and ADCs are showing more and more promising therapeutic outcome. Creative Biolabs is committed to ADCs design and development for more than ten years. Now we provide the best biparatopic ADC construction services against HER2 with first-class antibody-drug conjugate platforms, and we promise to apply our first-hand expertise to your distinct project requirements. Our comprehensive ADCs development services include ADC Antibody Screening, DrugLnk™ Custom Synthesis, Antibody Design and Conjugation, ADC in vitro Analysis, and ADC in vivo Analysis. If you are interested in our services, please do not hesitate to contact us for more details.

References

  1. Damelin, M. Innovations for Next-Generation Antibody-Drug Conjugates. Humana Press. 2018.
  2. Li, J. Y.; et al. A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer cell. 2016, 29(1): 117-129.

For Research Use Only. NOT FOR CLINICAL USE.


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