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Biopharmaceutical
surface and are rapidly proteolyzed by trypsin immobilized on 200 We envision that this technology will provide wide adaptation
nm diameter of nanoparticles. Using the difference of two particle of mAb quantification that is easy to adopt in clinical settings by
size, immobilized trypsin has physicochemically limited access to installing nSMOL with an automated system, and that will con-
the Fab of IgGs on the Protein A resins. Therefore, the signature tribute to the mAb development and therapeutic optimization for
peptides that identified the specific structure of each IgG Fab can many human diseases, such as cancers, autoimmune, infectious,
be efficiently harvested, and as a result, the peptide number to be and metabolic diseases.
brought to the subsequent multiple reaction monitoring (MRM)
with LC-MS analysis can be reduced. Since the development of
nSMOL in 2014, we have established the quantification method for References
2
more than 40 mAbs or Fc-fusion proteins . 1. Iwamoto, N., et al., Selective detection of complementarity-deter-
mining regions of monoclonal antibody by limiting protease access
In two collaborative studies with Providence Cancer Institute
to the substrate: nano-surface and molecular-orientation limited
for the innovative cancer immunotherapy, the serum trough levels proteolysis. Analyst, 2014. 139(3): p. 57680.
of mAb were measured using nSMOL method in patients with ad-
2. Iwamoto, N. and T. Shimada, Structure-Indicated LC-MS/MS Bioanalysis
vanced melanoma or head and neck squamous cell carcinoma re- of Therapeutic Antibodies. Methods Mol Biol, 2022. 2313: p. 187205.
3, 4
ceiving pembrolizumab or ipilimumab . The analytical conditions
3. Curti, B.D., et al., Enhancing clinical and immunological effects of
of each mAb using nSMOL method were validated according to anti-PD-1 with belapectin, a galectin-3 inhibitor. J Immunother
the Bioanalytical Method Validation Guidance for Industry issued Cancer, 2021. 9(4).
by the US FDA. We have successfully established assays to quan- 4. Koguchi, Y., et al., Trough levels of ipilimumab in serum as a poten-
tify both these mAbs in serum, with the lower limits of quantifica- tial biomarker of clinical outcomes for patients with advanced mela-
noma after treatment with ipilimumab. J Immunother Cancer, 2021.
tion using conventional LC-MS of 0.5 ug/mL for pembrolizumab
9(10).
and 1 ug/mL for ipilimumab, respectively. The medical statistics of
the relationship between clinical findings and the trough levels of
mAbs in serum indicated that the therapeutic mAb monitoring can
About Providence Cancer Institute
2, 3
be a potential biomarker for cancer immunotherapy .
Providence Cancer Institute, a part of Providence St. Joseph Health, offers
Our findings demonstrate the importance of monitoring the the latest in cancer services, including diagnostic, treatment, prevention,
trough levels of more immune checkpoint inhibitor mAbs in serum education, support and internationally renowned research. Providence
Cancer Institute is home to the Earle A. Chiles Research Institute, a world
for cancer immunotherapy. In recent years, the antibody-based
class research facility located within the Robert W. Franz Cancer Center
therapeutics for the treatment of cancer are becoming more and in Portland, Oregon, and is a recognized leader in the field of cancer
more diverse, supported by the active development of mAbs. immunotherapy since 1993. Investigators lead more than 400 active clin
ical trials in key areas such as cancers of the: breast, colon/rectum, pros
Under this context, a technology such as nSMOL, which can be
tate, lung, esophagus, liver and pancreas, head and neck, ovary, skin and
used for universal mAbs, can perform multiplex measurements, blood. Other studies are investigating treatments for COVID19.
and ensures very sufficient reproducibility, and will be indispensa- Learn more
ble not only for therapeutic mAb monitoring but also for pharma- http://www.providenceoregon.org/cancer/
cokinetic studies.
Drs. Fox, Tran, Koguchi (Providence Cancer Institute), Shimada, Iwamoto (Shimadzu)
Shimadzu Journal vol.9 Issue2 62
