ADC Development Services Targeting Notch3

With a world-class technical team, Creative Biolabs provides customized antibody-drug conjugate (ADC) development services for clients. Besides individual function service packages, Creative Biolabs also provides all-in-One ADC development service package from antibody generation to ADC filing.

Notch pathway is a potential target in the development of new approaches for the treatment of Notch3-expressing breast cancer. Since Notch3 expression is linked to cancer cell seeding and development of breast cancer metastases, Creative Biolabs now offers a variety of prepared anti-Notch3 ADC products and customized anti-Notch3 development services to serve your course of ADC development.

Introduction of Notch3

The Notch3 receptor is a highly conserved, type I, transmembrane glycoprotein. It regulates cell proliferation, differentiation, and survival in different tissues through the transcriptional activity of its intracellular domain. Notch3 undergoes ligand-dependent and ligand-independent internalization, and it traffics to lysosomes for degradation. Constitutive activation of Notch3 signaling may be oncogenic, leading to tumor induction in experimental mouse models. Besides, a number of studies have demonstrated Notch3 overexpression or amplification in malignant cells, including breast, ovarian, and lung cancer cells. Conversely, knockdown of the Notch pathway resulted in sensitization of breast cancer cells to deionizing radiation and cell death particularly in HER2-negative cells, suggesting that Notch inhibition may antagonize survival signals in breast cancer-initiating cells.

Fig.1 Structural organization of Notch1-4. (Wu, 2007)

Anti-Notch3 ADC in Breast Cancer

PF-06650808 is a novel anti-Notch3 ADC, comprised of a humanized IgG1 monoclonal antibody (mAb) linked to an auristatin-based cytotoxic payload with a cleavable maleimidocapronic-valinecitruline-p-aminobenzylooxycarbonyl (vc) linker, which was developed to treat patients with advanced solid malignancies. PF-06650808 is expected to bind selectively to Notch3-expressing tumor cells and release its cytotoxic payload after internalization and trafficking to vesicles rich in proteolytic enzymes, such as cathepsin B, that is able to cleave the vc-linker. In the first-in-human, dose-finding, phase I study (NCT02129205), scientists investigated the safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer. The results have shown that PF-06650808 effectively inhibited tumor growth in an orthotopic model of triple-negative breast cancer (TNBC).

Fig.2 An anti-Notch3 ADC example. (Nadkarni, 2018)

What Can We Do for You?

Scientists at Creative Biolabs are highly skilled in the design and synthesis of a variety of toxins and linkers based on our DrugLnk™ Custom Synthesis platform. Armed with our diverse antibody preparation platforms and ADC Antibody Screening platform, our biologics team is able to provide the most suitable mAbs for ADC development. Based on the former experience in preparing anti-Notch3 ADC products, Creative Biolabs has optimized the development formulation and our process optimization studies resulted in the formation of the conjugates with a low level of aggregates. Creative Biolabs has also explored and adopted a variety of methodologies in Antibody Design and Conjugation to introduce a series of specific and chemically versatile conjugation sites into the antibody sequences to achieve a narrower DAR. ADC in vitro Analysis and ADC in vivo Analysis services are also optional according to your demands.

All ADC-related functions and developments services are fully supported with a well-equipped, state-of-the-art analytical facility. If you are interested in our ADC development services targeting Notch3, please feel free to contact us for more information.

References

1. Wu, J.; Bresnick, E. H. Bare rudiments of notch signaling: how receptor levels are regulated. Trends in biochemical sciences. 2007, 32(10): 477-485.
2. Nadkarni, D. V.; et al. Process Development and Structural Characterization of an Anti-Notch 3 Antibody-Drug Conjugate. Organic Process Research & Development. 2018, 22(3): 286-295.

For Research Use Only. NOT FOR CLINICAL USE.