2 research outputs found
Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond
In the era of precision medicine, antibody-based therapeutics are rapidly enriched with emerging advances and new proof-of-concept formats. In this context, antibody-drug conjugates (ADCs) have evolved to merge the high selectivity and specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of attached payloads. So far, ten ADCs have been approved by FDA for oncological indications and many others are currently being tested in clinical and preclinical level. This paper summarizes the essential components of ADCs, from their functional principles and structure up to their limitations and resistance mechanisms, focusing on all latest bioengineering breakthroughs such as bispecific mAbs, dual-drug platforms as well as novel linkers and conjugation chemistries. In continuation of our recent review on anticancer implication of ADC’s technology, further insights regarding their potential usage outside of the oncological spectrum are also presented. Better understanding of immunoconjugates could maximize their efficacy and optimize their safety, extending their use in everyday clinical practice
Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review
More than 40 tyrosine kinase inhibitors (TKIs) have received
hematological or oncological indications over the past 20 years,
following the approval of imatinib, and many others are currently being
tested in clinical and preclinical level. Beyond their common
toxicities, no certain agent from this large class of molecularly
targeted therapies was strongly associated with “off-target”
impairment of neuromuscular transmission, and although myasthenia gravis
(MG) is a well-characterized autoimmune disorder, only few sporadic
events proven by serologically detected causative autoantibodies and/or
by positive electrophysiological tests are reported in the literature.
Herein, we present the first case of anti-MUSK (+) MG in a woman with
metastatic BRAF-mutant melanoma after long-term treatment with
dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by
this report, a systematic literature review was conducted, summarizing
all other cancer cases that developed MG, after exposure to any type of
targeted agent and regardless of the underlying malignancy. All
available data on the clinical diagnosis, the potential of administered
TKIs to induce a seropositive myasthenic syndrome, the immune and
non-immune-mediated pathogenesis of postsynaptic damage, and the
challenging management of this neuromuscular toxicity were collected and
discussed. In the presented case, MG was confirmed by both
autoantibodies and nerve-conduction tests, while its reactivation after
TKIs rechallenge supports a more than coincidental association. The
following review identified 12 cancer cases with TKI-related MG in six
case reports and one case series. In most of them, the myasthenia
diagnosis was challenging, since the clinical symptomatology of
fatigable weakness was not corroborating with consistent laboratory and
electrophysiological findings. In fact, anti-AchR titers were positive
in five and anti-MuSK only in the abovementioned individual. The
symptomatology corresponded to TKI discontinuation and standard
treatment with pyridostigmine and prednisolone; intravenous
immunoglobulin was added only in three, and two required mechanical
ventilation. In an era where TKIs will be prescribed more frequently for
various malignancies, even in combinations with immune-checkpoint
inhibitors, this report synthesizes their risk for neuromuscular
complications and increases the clinicians’ awareness in order to extend
the on-treatment and overall survival of TKI-treated cancer
patients.</p>