Antibody-Drug Conjugates
Antibody-Drug Conjugates
Ashutosh A. Kulkarni 0 1
Hovhannes J. Gukasyan 0 1
0 Pfizer Inc , San Diego, CA , USA
1 Celgene Corporation , San Diego, CA , USA
2 Ashutosh A. Kulkarni
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Antibody-drug conjugates (ADCs) are an exciting and new class
of therapeutic modalities that have gained significant traction
over the past few years – specifically in the field of oncology.
With the recent approvals of CD-30 directed Adcetris®
(brentuximab vedotin) and the Her2 targeted Kadcyla®
(ado-trastuzumab emtansine) and hundreds of other ADCs in
various stages of drug discovery and development, the field is
experiencing significant optimism and interest from the
biopharmaceutical industry. Several esteemed organizations
including Celgene, Immunogen, Pfizer, Agensys, and
Genentech – to name a few – are investing significant resources
into ADC discovery and development. The lure of ADCs is that
they combine the specificity of a monoclonal antibody with the
potent cytotoxicity of a small molecule toxin payload. The
hypothesis is that by combining these 2 characteristics, one should
be able to specifically target the ADC to the diseased tissue and
steer clear of the non-specific toxicity of the toxin payload. Also,
the presence of the toxin payload would make the ADC
significantly more efficacious compared to antibody alone. One of the
key benefits is that the antibody does not necessarily need to have
therapeutic activity on its own since the efficacy of ADC is driven
by internalization of the ADC molecule→trafficking to the
lysosome→degradation to the final catabolite→cytotoxic activity of
the catabolite on the cellular machinery.
However, ADCs require multi-parameter optimization,
which is one of the key challenges in their discovery and
development effort. In fact, significant investment is placed
during ADC discovery in identifying a viable target. The target is
studied for its cellular trafficking, internalization
characteristics (a necessity for ADCs), and its expression profile to ensure
that it is unique to the target tissue and has little to no
expression in normal tissues. Dr Ben Xu, Dr Kate Lai, and Dr Puja
Sapra have contributed excellent articles to this theme issue
that focus on these very topics. Another aspect of the
multiparametric optimization is the selection of appropriate linker
and toxin payload combination. Selection of the appropriate
linker and toxin payload is critical to achieving the required
efficacy without giving rise to significant systemic toxicity.
Important questions include: 1) which type of linker is suitable for
the target of choice – cleavable or non-cleavable? 2) what is
the impact of attaching a linker and payload to the
conjugation site on the antibody? 3) which conjugation site on the
antibody is ideal for covalent attachment of linker and
payload? Dr Bruce Tomczuk has contributed a very informative
article on the linker-payload chemistry aspects. In addition,
Dr Roger Pak has also contributed a revealing article on the
physicochemical considerations that have an impact on the
formulation design and technology of ADCs.
Heterogeneity has been one of the Achilles heel in ADC
drug discovery and development. Not only does it lead to
analytical challenges in terms of quantitative or qualitative
biophysics and chemistry, but it also leads to scale up and
production challenges in late development making it very costly and
time consuming. This is partly offset, however, by the high
potency and selectivity of ADCs which translates to relatively
lower therapeutic doses and drug substance, drug product
requirements. As a result, site specific and well controlled
conjugation approaches have been developed to make the ADCs
more homogenous with well characterized drug-antibody
ratios (DAR). In addition, cell-free systems are being utilized for
production of antibodies to eliminate post-translational
modifications and confer more homogeneity, better stability, as well
as better pharmacokinetic characteristics on the ultimate ADC
molecule. Dr Gang Yin’s article on this aspect is cutting edge
and an excellent addition to this theme issue.
The optimized ADC candidates are evaluated in
preclinical ADMET studies as well as efficacy models. The ADMET
studies for ADCs are generally more complex than those of
small molecules or biologics, mainly because they combine
both aspects into one. The analytical assays needed for ADC
studies span the whole gamut of ligand binding assays (ELISA,
Meso Scale) all the way to protein mass spectrometry.
Logistics of sample processing and analysis are more involved and
require multiple, special considerations. The ADME
properties are also a hybrid of disposition characteristics of small
molecules and those of biologics, making it very challenging
to predictably translate data from preclinical species to man.
Significant advances are being made in bioanalytical aspects
as well as PKPD modeling and Dr Dowdy Jackson, Dr Dhaval
Shah, and Dr Amrita Kamath have contribu (...truncated)