Development of Biparatopic CD38-targeted Bispecific ADCs

Antibody-drug conjugates (ADCs) as an innovative therapeutic strategy continue to show significant promise. ADCs provide a compelling combination of high specificity and therapeutic efficacy by targeting antigens that are differentially overexpressed in tumor cells while minimizing exposure of healthy tissue. With the approval of two bispecific antibodies (BsAbs), BsAb has been studied more frequently for therapeutic applications. Recently, researches demonstrated that BsAbs approaches can be used to generate ADCs with better efficacy and safety profile than conventional ADC formed with a monovalent antibody.

As a leader in the field of antibody discovery and bioconjugation services, Creative Biolabs focuses on novel ADCs design and construction. Now we provide comprehensive bispecific biparatopic ADCs development services targeting CD38 with our state-of-art technology platforms. Our services include synthetic route design and optimization, complex conjugates production, and characterization. We are confident to offer high-quality and cost-effective ADCs service for our clients.

Introduction of CD38

CD38 (cluster of differentiation 38, cyclic ADP ribose hydrolase) is a 45 KDa surface glycoprotein present on the surface of many immune cells including CD4⁺, CD8⁺, B lymphocytes, and natural killer cells. It is first identified as an adhesion molecule, able to interact with endothelial CD31. CD38 protein is encoded by the CD38 gene located on chromosome 4 in humans. CD38 plays important role in cell adhesion, signal transduction, and calcium signaling. CD38 is a glycoprotein with ectoenzymatic functions involved in the metabolism of extracellular nicotinamide adenine dinucleotide (NAD⁺) and cytoplasmic nicotinamide adenine dinucleotide phosphate (NADP). It is overexpressed on myeloma cells while relatively low on normal lymphoid and myeloid cells and non-hematopoietic tissues. Thus, CD38 is considered as a good target for novel multiple Myeloma (MM) therapeutic strategies such as mAbs, radioimmunotherapy, and adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38.

Fig.1 Role of CD38 in NAD⁺ metabolism. (Hogan, 2019)

Biparatopic CD38-targeted Bispecific Antibody

The natural variable domain of heavy chain antibodies in camelids is called VHH or sdAb. sdAbs exhibit several advantages over conventional antibodies. The single-domain format of sdAbs greatly facilitates the construction of bispecific and biparatopic dimers by genetically linking two sdAbs with a flexible peptide linker. A bispecific and biparatopic sdAb against CD38 has been developed that recognize distinct epitopes of CD38, which is a genetic fusion of a sdAb to the hinge, CH2, and CH3 domains of human IgG1 forms highly soluble llama/human chimeric heavy chain antibodies (hcAbs). The biparatopic dimers showed better tissue penetration than conventional antibodies. Results showed that the combination of two CD38 hcAbs elicits potent complement-dependent cytotoxicity (CDC) to tumor cells. Besides, the biparatopic hcAbs show higher CDC potency and therefore hold promise as novel therapeutics for the treatment of multiple myeloma.

Studies showed that both ADC and biparatopic antibody targeting CD38 are presenting significant anti-tumor activity, the combination of them to produce a novel biparatopic CD38-targeted bispecific ADC may represent a more potent therapeutic method for CD38-positive cancers.

Fig.2 Combining two sdAbs directed to distinct epitopes of CD38 in a biparatopic hcAb induces potent CDC. (Schütze, 2018)

What Can We Do for You?

Creative Biolabs is a leading company in the area of ADCs development and has completed a large number of ADC-related projects. We presently provide a comprehensive bispecific biparatopic ADCs design, construction, and analysis services to help clients promote the anti-CD38 bispecific ADC development project. We are more than happy to apply first-hand expertise to your distinct project requirements. If you are interested in our services, please contact us for more information.

Our featured ADCs development services including:

• ADC Antibody Screening
• DrugLnk™ Custom Synthesis
• Antibody Design and Conjugation
• ADC in vitro Analysis
• ADC in vivo Analysis

References

1. Hogan, K. A.; et al. The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging and metabolic diseases. Frontiers in immunology. 2019, 10: 1187.
2. Schütze, K.; et al. CD38-specific Biparatopic heavy chain antibodies display potent complement-dependent cytotoxicity against multiple myeloma cells. Frontiers in immunology. 2018, 9: 2553.

For Research Use Only. NOT FOR CLINICAL USE.