Tackling solid tumour therapy with small-format drug conjugates.

The pharmacokinetic-pharmacodynamic relationship is extremely complex and tumour drug penetration is one key parameter influencing therapeutic efficacy. In the context of antibody-drug conjugates (ADCs), which has undergone many innovation cycles and witnessed many failures, this feature is being addressed by a number of alternative technologies. Immunoglobulin-based ADCs continue to dominate the industrial landscape, but smaller formats offer the promise of more-effective cytotoxic payload delivery to solid tumours, with a higher therapeutic window afforded by the more rapid clearance.

Current strategies for the discovery and bioconjugation of smaller, targetable drug conjugates tailored for solid tumor therapy.

: Antibody-Drug Conjugates (ADCs) have undergone a recent resurgence with 5 product approvals over the last 2 years but for those close to the field, it's been repeated cycles of setbacks and new innovations. A new wave of innovation is in the type of format used to deliver the cytotoxic payloads, with smaller bio-molecules being designed to have more optimal penetration and elimination properties tailored for solid tumors.: In this review, the authors cover many of the recently described smaller-format drug conjugates (including formats such as diabodies, Fabs, scFvs, domain antibodies) with an emphasis on the types of conjugation technologies used to attach the chemical linker-payload.

Miniaturised 'antibody'-drug conjugates for solid tumours?

With Antibody-Drug Conjugate strategies firmly focussed on the precise conjugation to the large protein Immunoglobulin-G format, it is easy to miss the more recent technological innovations in small-format drug conjugates. Here, the targeting ligand can be at 50-95% reduced in size, or even smaller if peptidic in nature. Antibody domains or alternative binding scaffolds, chemically-modified with ultra-potent cytotoxic payloads offer an alternative approach for oncology therapeutics, promising a wider therapeutic window by virtue of superior solid tumour penetration properties and more rapid system clearance.

Using antibody directed phototherapy to target oesophageal adenocarcinoma with heterogeneous HER2 expression.

Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity.

Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?

Antibody-Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK).