Antibody drug conjugates for glioblastoma: current progress towards clinical use

ABSTRACT

Introduction

Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors.

Areas covered

This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors.

Expert opinion

ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.

KEYWORDS:

• Gliomas
• blood–brain barrier
• antibody drug conjugates
• biomarkers
• Brain tumours

Article highlights

• To date, antibody drug conjugates (ADCs) in brain tumors have targeted a range of targets, especially EGFR and its receptors, to deliver a variety of payloads including immunotoxins, radioisotopes, and cytotoxic agents against intracellular targets like DNA and the tumor cytoskeleton

• Trials to date have been negative in unselected populations or populations selected only for target expression by tissue-based assays, with emerging data suggesting that identifying populations with enhanced susceptibility to current ADCs may require more novel assays and techniques

• Improving BBB penetration will be a key strategy that is required to increase the efficacy of these drugs in patients with primary brain tumors, whether though innovation in ADC design or through adjunctive strategies

• Optimal development of ADCs for brain tumors will likely require PK/PD assessment in early phase testing and combinatorial strategies are starting to emerge to deal with the problems of heterogeneity that is another key barrier to their use.

Declaration of interest

HK Gan and AM Scott have had previous consultancy roles and/or research support with AbbVie. AM Scott has received research support from Humanigen. AM Scott is an inventor on patents relevant to ABT-806 and Ifabotuzumab. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.