The full potential of many drugs remains unrealized as a result of suboptimal delivery to target cells, or problems getting them to where they need to be once inside the cell. This means that higher doses are needed to achieve a therapeutic effect, increasing the likelihood of treatment-limiting side effects.
Antibody–drug conjugates (ADCs) are a case in point. These biologics are highly effective at delivering therapeutic agents to cells expressing specific surface antigens, but what happens next stymies their ability to achieve maximal therapeutic benefit. When ADCs bind to the surface of a target cell, they are brought inside by endocytosis, and can accumulate within endosomes rather than reaching the desired subcellular location. This endosomal trapping limits the release and activity of the cytotoxic payload, ultimately restricting the therapeutic potential of ADCs.
The problem of endosome entrapment is a well-known challenge for increasing the efficacy of ADCs without increasing dosing levels. Defence Therapeutics has developed the Accum technology platform to solve this issue and unleash the full potential of current and future ADCs (Fig. 1).
Fig. 1 | Escaping the endosome to reach the intracellular target. Unmodified antibody–drug conjugates (ADCs) can become trapped in endosomes (lower panel). When combined with the Accum molecule, ADCs are effectively able to escape from these organelles (top).
Taking inspiration from nature
The Accum technology was inspired by a finding from the natural world. Viruses—in common with ADCs—bind to the surface of cells before entering them through endocytosis and accumulating in endosomes, preventing them from reaching the cytosol where viral replication can take place.
However, some enteric viruses have evolved a means of escaping this fate by exploiting the presence of bile acids encountered in the intestine. They carry the acids with them as they become engulfed in endosomes, resulting in acidifi-cation of the organelles. This in turn activates the acid sphingomyelinase (ASM) enzyme and the production of ceramide, which destabilizes the endosomal membrane, inducing the formation of transient pores. These allow the viral particles to escape into the cytosol while preserving the integrity of the host cell.
Targeted intracellular delivery
The unique Accum molecule has been designed to attach to ADCs and other payloads to dramatically enhance intracellular delivery. It consists of two synergistic components: cholic acid (ChAc), which activates ASM; and a nuclear localization signal (NLS), which works with ChAc to drive efficient payload extrusion through the pores. When combined, these elements significantly boost delivery and improve the effective drug dose, with studies showing that using Accum technology can enhance the effects of existing ADCs by up to fifty-fold.
By increasing the proportion of the therapeutic agent that is able to work in the cell, the Accum platform offers the possibility of dramatically reducing the dose of ADCs required to see clinically beneficial effects. Many ADCs have shown promising efficacy in early-stage studies, only to fail in the clinic due to dose-limiting toxicities; such drugs could be rescued from failure by combining them with the Accum molecule. And for new ADCs in development, the Accum platform can improve efficacy at a given dose and de-risk clinical-stage development by reducing toxicity and side effects.
Joining forces to maximize benefit
Defence Therapeutics welcomes talks with potential collaborators and partners to explore the possibilities that the Accum platform offers—from rescuing failed drugs, to improving the performance of US Food and Drug Administration (FDA)-approved drugs that have toxicity-associated limitations, and expediating the progress of investigational new drugs in early-stage development.