16 BioPharm International
®
Emerging Therapies eBook September 2024 www.biopharminternational.com
O
ver the past several decades, bioconju-
gate therapeutics, which unite synthetic
chemistry with biological mechanisms,
have gained immense interest in research
and drug development. Antibody-drug conjugates
(ADCs) represent the most prominent class within
this modality. Fifteen ADC therapeutics have been
approved by FDA since 2000, and more than 150
clinical trials are currently active, roughly 12% of
which are late-phase (1). Comprised of a monoclo-
nal antibody (mAb) and a cytotoxic drug compound
joined by a linker molecule, ADCs are promising as
a novel cancer treatment strategy that enables tar-
geted delivery of potent chemotherapeutic agents
while sparing healthy cells and reducing systemic
toxicity. However, challenges with off-target toxici-
ties of early ADC candidates slowed the expansion of
the field and underscored the importance of linker
design in drug safety and efficacy. It is now well-es-
tablished that linker chemistry and bioconjugation
strategies play fundamental roles in the controlled
delivery of cytotoxic drugs, presenting new com-
plexities as researchers and drug developers work to
optimize ADC performance and deploy linker tech-
nology at clinical and commercial scale.
Unraveling the intricate role of
linker design in ADC performance
The function of a linker extends far beyond simply
attaching a drug and antibody. It is well-known that
the stability of an ADC and the mechanism of payload
release can impact ADC performance, and most drug
developers recognize that the choice of cleavable or
non-cleavable triggers is one of the first decisions to
consider. Cleavable linkers employ a chemical or en-
zymatic trigger within their structure that enables
efficient cleavage for controlled drug release within
the tumor target. Conversely, non-cleavable linkers
do not incorporate a trigger but instead rely on inter-
nalization by endocytosis and lysosomal processing
Pamela James, PhD, is
vice-president, Product,
at Vector Laboratories.
ADDMESHCUBE
-
STOCK.ADOBE.COM
Valuing Specialized
Experience in ADC
Development
Bringing promising ADC candidates to market faster hinges
on the biopharma industry investing in linker design capabilities.
