Bispecific ADCs Development

Bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in various clinical studies, showing improved drug selectivity and efficacy. The selectivity, internalization, payload delivery efficiency and acquired resistance of ADC can be greatly benefited from bispecific approaches, the generation of bispecific ADCs. Based on the well-established ADC and bsAb platforms, Creative Biolabs offers customized bispecific ADCs development services to help you optimize your ADC.

The Overview of Bispecific ADCs

ADCs are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place are therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. This limitation can be overcome by enhancing lysosomal ADC delivery via a bispecific approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment.

Fig.1 Schematic bispecific ADC.

The antibody component of a bispecific ADC is responsible for high tumor specificity and needs to be effectively internalized to deliver the payload inside the cancer cell. Many efforts have been made to optimize bispecific antibody affinity, selectivity, and pharmacokinetics to improve tumor delivery. Bispecific antibodies with strong binding to a target show high accumulation in the tumor but exhibit poor tumor penetration so a careful balancing act is required to achieve optimal therapeutic efficacy. Bispecific ADCs are in development as a viable route to increase tumor selectivity while retaining highly potent antitumor efficacy. For example, bispecific ADCs directed against c-MET and EGFR displayed efficacious killing of EGFR and c-MET overexpressing cancer cells with reduced toxicity in normal cells expressing EGFR.

Fig.2 The process of bispecific ADCs exerting activity.

Bispecific ADCs Development Services at Creative Biolabs

Several bispecific ADC approaches have been developed by Creative Biolabs to enhance internalization and trafficking to the lysosome, thus maximizing the amount of drug that is effectively delivered to tumor cells at a given dose.

• Fast-internalizing Receptor-based Bispecific ADCs

This approach consists of utilizing one arm of the bispecific to target an existing fast internalizing receptor that promotes trafficking to lysosome and degradation of the complex, whilst the second arm is used to enable specific binding to the surface of the target tumor cell. This approach alleviates the need to focus solely on internalizing and non-fast-recycling targets for cancer therapy but still requires the presence of a strongly internalizing target on the cell surface to “drag” the other antigen and transfer it to the lysosome. For example, the bispecific ADCs simultaneously targets the HER2 and PRLR double positive breast cancer cells to enhance the internalization and activity of the ADC, and to decrease the off-target toxicities to the healthy cells.

• Biparatopic Receptor-based Bispecific ADCs

Another and more general approach to increase internalization and trafficking to the lysosomes consists of simultaneously targeting two different epitopes on the same antigen with a bispecific entity (e.g. a biparatopic antibody). This can not only increase selectivity towards cancer cells but it can also lead to enhanced internalization and trafficking to the lysosome by inducing clustering and cross-linking of receptors. The past few years have seen an increase in the development of biparatopic platforms to promote receptor lysosomal trafficking; this approach is now also gathering momentum in the ADC field. For example, an anti-HER2 biparatopic antibody displayed better internalization, lysosomal trafficking, and degradation of the antibody-antigen complex relative to the traditional T-DM1.

At Creative Biolabs, we can offer the following bispecific ADCs development services:

1. Selection of epitope/receptor combinations: fast-internalizing receptor, biparatopic receptor
2. Identification of bispecific antibody formats: bivalent bispecific antibodies, tetravalent multispecific antibodies
3. Generation of bispecific ADC
4. In vitro and in vivo evaluation of bispecific ADC

Creative Biolabs has been involved in the development of ADCs for many years and we are committed to completing your project with high quality. We can provide you with the best services to ensure your requirements are met. If you are interested in our bispecific ADCs development services, please contact us for more details.

For Research Use Only. NOT FOR CLINICAL USE.