Fast-internalizing Receptor-based Bispecific ADCs

In recent years, bispecific antibody-drug conjugates (ADCs) have been developed as a promising and effective therapeutic agent for a variety of cancer therapies. Bispecific ADCs possess unique advantages such as the dual antigen target and potent antitumor activity compared with other traditional therapeutic options. With extensive experience in linker-payload synthesis, antibody production, and conjugation technology, Creative Biolabs has constructed a mature system for bispecific ADCs design and construction. Our services will effectively save the time and cost of your discovery programs by taking advantage of our expertise and innovative technology platforms.

The Mechanisms of ADC Internalization

An ideal ADC requires efficient internalization and trafficking to lysosomes to be efficacious. Even with a target highly expressed on a cell surface, if the ADC cannot enter the cell to deliver the payload, the treatment will have limited effect. Molecules can be internalized from the surface of eukaryotic cells through a wide array of mechanisms. These include clathrin-independent mechanisms such as phagocytosis, macropinocytosis, and caveolin-dependent endocytosis or clathrin-dependent mechanisms such as receptor-mediated endocytosis. Clathrin-dependent endocytosis is the best characterized and predominant mechanism for the internalization of cell surface receptors and thus provides an ADC with a cell-specific entry mechanism.

Fig.1 Possible Intracellular trafficking routes of ADCs. (Ritchie, 2013)

Receptors such as the HER2 continuously recycle back to the plasma membrane immediately after cellular internalization. HER2 is a good target candidate for ADCs. As HER2 is internalized, it provides an entry point for lysosomal delivery of cargos. However, HER2 is also very efficiently recycled back to the plasma membrane, thus when HER2-targeted ADCs bind to their target, they are internalized but mostly do not reach the lysosome, they are recycled, which greatly limits drug release and the overall efficacy of the treatment. This rapid endocytic recycling and limited lysosomal trafficking is a key issue and has been put forward as one of the potential reasons for the disappointing clinical results in several trials of ado-trastuzumab emtansine (T-DM1), an anti-HER2 ADC. When developing an ADC against receptors such as these, one could plausibly attempt to change antibody dissociation within the endosome in an attempt to reduce the likelihood that the ADC will cycle back out of the cell with its receptor.

Development Services of Bispecific ADCs Based on Fast-internalizing Receptor

The ideal tumor target for an ADC has the following features: (1) the antigen is abundantly and exclusively expressed on the target cell, (2) it undergoes minimal secretion since secreted receptors can bind the antibody in the circulation, thus limiting exposure to the target cell, (3) it possesses an appropriate rate of endocytosis and (4) it undergoes an appropriate intracellular trafficking route for the desired outcome.

Fast-internalizing receptor-based bispecific ADCs development services at Creative Biolabs include the following receptors:

With years’ experience in the field of ADC and bispecific antibody development, Creative Biolabs is committed to providing clients high-quality bispecific ADCs design and construction services in a time and cost-efficient way. If you are interested in our fast-internalizing receptor-based bispecific ADCs development services, please contact us for more details.

Reference

1. Ritchie, M., et al. January. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. In MAbs (Vol. 5, No. 1, pp. 13-21). 2013, Taylor & Francis.

For Research Use Only. NOT FOR CLINICAL USE.