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Antibodies
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Monoclonal Antibody-Directed Therapy Series II
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Monoclonal Antibody-Directed Therapy Series II

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 53626

Special Issue Editors

Dr. Amita Datta-Mannan

E-Mail
Guest Editor
Exploratory Medicine & Pharmacology, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46225, USA
Interests: monoclonal antibodies; ADCs; bispecifics; fusion proteins; antibody engineering; drug disposition; distribution; pharmacokinetics; modeling and simulation; physical–chemical characterization; mechanisms influencing clearance of antibody products
Special Issues, Collections and Topics in MDPI journals
Dr. Brooke Rock

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Co-Guest Editor
Amgen, San Francisco, CA, USA
Interests: pharmacokinetics; drug metabolism; enzymology; PK/PD modeling

Special Issue Information

Dear Colleagues,

The unparalleled specificity and high efficacy of monoclonal antibodies (mAbs) make them the most desirable products as biological medicines. They are among the top-selling drugs globally, and their market size continues to grow annually. There are only about 70 mAb products on the market currently, but considering the hundreds that are in clinical trials and the new advancements in this field, such as the development of biosimilars, their market share is expected to increase substantially in the near future.

Over the years, different types of mAb products have been developed, including full-size mAbs, antibody fragments, antibody–drug conjugates (ADC), and bispecifics, but full-size mAbs still dominate the market. In addition, new approaches such as PEGylation or the hyperglycosylation of constant domains of mAbs and other forms of antibodies such as single domain antibodies (nanobodies) and antibody-targeted nanoparticles have also been frequently explored, and they seem to be promising, but these products are yet to receive approval and reach the market.

The majority of biologics, in particular mAbs, are expensive due to the high costs associated with their development and manufacturing, and thus, their similar follow-on counterparts—biosimilars—are expected to be very attractive to many consumers because of their affordability. The development of biosimilars has recently become possible for many blockbuster biologics owing to the loss of their patent protection and updates in regulatory guidelines.

Some antibody products are closely related to the reference product, but because they have superior characteristics compared to the former, they are called ‘biobetters’. These next-generation products are not defined well at the moment, but perhaps some existing products such as ADCs, bispecifics, and PEGylated or hyperglycosylated versions of certain products can be called biobetters. Biobetters may display improved efficacy/specificity, bind to more than one target, or tackle some commonly observed physical–chemical issues such as protein aggregation. Advances in connecting the mechanisms influencing the disposition and pharmacokinetics of mAb products will continue to augment the discovery and development of antibody products. Immunogenicity and immunogenic potential remain a key space for the optimization of antibody products as therapeutic modalities.  

These new developments and other advances such as in silico methods employed to study and/or predict protein–protein interactions require frequent updates in the literature and necessitate the publication of a Special Issue such as this one. We strongly believe this is a timely endeavor and would like to invite researchers from both academia and industry to submit their novel mAb therapy work for this issue in order to capture the new developments that have transpired as well as established concepts in this exciting field. In this Special Issue, we will consider the following topics: mAb therapeutics, novel forms of antibody products, optimization or mAbs with experimental or computational methods including novel pharmacokinetic modeling and simulation approaches, advances in pharmacokinetic characterization, disposition, biodistribution and clearance of antibody products, approaches toward immunogenicity prediction/characterization, and new topics including but not limited to bispecifics, ADCs, nanobodies, and antibody-targeted nanoparticles.

Dr. Amita Datta-Mannan
Dr. Brooke Rock
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • monoclonal antibody (mAb) therapies
  • antibody medicines
  • antibody drug conjugates (ADCs)
  • bispecific and multispecific antibodies
  • next-generation biologics
  • follow-on biologics
  • single-domain antibodies—nanobodies
  • optimization of antibody products
  • formulation of mAbs
  • biosimilars
  • biobetters
  • antibody engineering
  • antibody pharmacokinetics
  • antibody distribution in vivo and in vitro
  • modeling and simulation of antibody clearance
  • physical–chemical characterization of antibody products
  • mechanisms influencing antibody clearance 

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Published Papers (12 papers)

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Research

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9 pages, 3396 KiB  
Communication
Establishment and Functional Characterization of Murine Monoclonal Antibodies Recognizing Neuritin
by Georgia Papadogianni, Inga Ravens, Ahmed Hassan, Andrew Flatley, Regina Feederle, Günter Bernhardt and Hristo Georgiev
Antibodies 2023, 12(2), 28; https://doi.org/10.3390/antib12020028 - 7 Apr 2023
Viewed by 2160
Abstract
Neuritin represents a neurotrophic factor that is not only important in neuronal development and plasticity but also impacts endothelial angiogenesis, cell migration, tumor growth and the production of antibodies by B cells. We established monoclonal mouse anti-mouse neuritin antibodies by immunizing knock-out mice [...] Read more.
Neuritin represents a neurotrophic factor that is not only important in neuronal development and plasticity but also impacts endothelial angiogenesis, cell migration, tumor growth and the production of antibodies by B cells. We established monoclonal mouse anti-mouse neuritin antibodies by immunizing knock-out mice with two different neuritin-derived peptides. Because neuritin is well conserved between species, these new monoclonal antibodies recognize the neuritin of a wide variety of species, including human. Moreover, they not only recognize specifically surface-bound neuritin expressed by murine follicular regulatory T cells but also the block binding of recombinant neuritin to germinal center B cells. This suggests that these newly generated tools will be of great use in studying neuritin expression and function. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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20 pages, 4761 KiB  
Article
Characterization of an IDH1 R132H Rabbit Monoclonal Antibody, MRQ-67, and Its Applications in the Identification of Diffuse Gliomas
by Raul Copaciu, Juliet Rashidian, Joshua Lloyd, Aril Yahyabeik, Jennifer McClure, Kelsea Cummings and Qin Su
Antibodies 2023, 12(1), 14; https://doi.org/10.3390/antib12010014 - 6 Feb 2023
Cited by 1 | Viewed by 3228
Abstract
The current diagnosis of diffuse glioma involves isocitrate dehydrogenase (IDH) mutation testing. Most IDH mutant gliomas carry a G-to-A mutation at IDH1 position 395, resulting in the R132H mutant. R132H immunohistochemistry (IHC), therefore, is used to screen for the IDH1 mutation. [...] Read more.
The current diagnosis of diffuse glioma involves isocitrate dehydrogenase (IDH) mutation testing. Most IDH mutant gliomas carry a G-to-A mutation at IDH1 position 395, resulting in the R132H mutant. R132H immunohistochemistry (IHC), therefore, is used to screen for the IDH1 mutation. In this study, the performance of MRQ-67, a recently generated IDH1 R132H antibody, was characterized in comparison with H09, a frequently used clone. Selective binding was demonstrated by an enzyme-linked immunosorbent assay for MRQ-67 to the R132H mutant, with an affinity higher than that for H09. By Western and dot immunoassays, MRQ-67 was found to bind specifically to the IDH1 R1322H, with a higher capacity than H09. IHC testing with MRQ-67 demonstrated a positive signal in most diffuse astrocytomas (16/22), oligodendrogliomas (9/15), and secondary glioblastomas tested (3/3), but not in primary glioblastomas (0/24). While both clones demonstrated a positive signal with similar patterns and equivalent intensities, H09 exhibited a background stain more frequently. DNA sequencing on 18 samples showed the R132H mutation in all IHC positive cases (5/5), but not in negative cases (0/13). These results demonstrate that MRQ-67 is a high-affinity antibody suitable for specific detection of the IDH1 R132H mutant by IHC and with less background as compared with H09. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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14 pages, 4130 KiB  
Article
A Defucosylated Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity in Xenograft Model
by Teizo Asano, Tomohiro Tanaka, Hiroyuki Suzuki, Guanjie Li, Tomokazu Ohishi, Manabu Kawada, Takeo Yoshikawa, Mika K. Kaneko and Yukinari Kato
Antibodies 2022, 11(4), 74; https://doi.org/10.3390/antib11040074 - 24 Nov 2022
Cited by 8 | Viewed by 2674
Abstract
The epithelial cell adhesion molecule (EpCAM) is a stem cell and carcinoma antigen, which mediates cellular adhesion and proliferative signaling by the proteolytic cleavage. In contrast to low expression in normal epithelium, EpCAM is frequently overexpressed in various carcinomas, which correlates with poor [...] Read more.
The epithelial cell adhesion molecule (EpCAM) is a stem cell and carcinoma antigen, which mediates cellular adhesion and proliferative signaling by the proteolytic cleavage. In contrast to low expression in normal epithelium, EpCAM is frequently overexpressed in various carcinomas, which correlates with poor prognosis. Therefore, EpCAM has been considered as a promising target for tumor diagnosis and therapy. Using the Cell-Based Immunization and Screening (CBIS) method, we previously established an anti-EpCAM monoclonal antibody (EpMab-37; mouse IgG1, kappa). In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and an antitumor activity by a defucosylated mouse IgG2a-type of EpMab-37 (EpMab-37-mG2a-f) against a breast cancer cell line (BT-474) and a pancreatic cancer cell line (Capan-2), both of which express EpCAM. EpMab-37-mG2a-f recognized BT-474 and Capan-2 cells with a moderate binding-affinity [apparent dissociation constant (KD): 2.9 × 10−8 M and 1.8 × 10−8 M, respectively] by flow cytometry. EpMab-37-mG2a-f exhibited ADCC and CDC for both cells by murine splenocytes and complements, respectively. Furthermore, administration of EpMab-37-mG2a-f significantly suppressed the xenograft tumor development compared with the control mouse IgG. These results indicated that EpMab-37-mG2a-f exerts antitumor activities and could provide valuable therapeutic regimen for breast and pancreatic cancers. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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15 pages, 5034 KiB  
Article
High-Resolution Epitope Mapping and Affinity Binding Analysis Comparing a New Anti-Human LAG3 Rabbit Antibody Clone to the Commonly Used Mouse 17B4 Clone
by P. Daniel Warren, Mark S. Dodson, Margaret H. Smith, Terry H. Landowski, John Douglas Palting and Penny Towne
Antibodies 2022, 11(4), 60; https://doi.org/10.3390/antib11040060 - 21 Sep 2022
Cited by 3 | Viewed by 2835
Abstract
Lymphocyte activation gene 3 (LAG3) is a T cell inhibitory receptor that promotes tumor cell immune escape and is a potential target for cancer diagnostic and immunotherapeutic applications. We used automated capillary electrophoresis (ACE), surface plasmon resonance (SPR), and immunohistochemistry (IHC) to compare [...] Read more.
Lymphocyte activation gene 3 (LAG3) is a T cell inhibitory receptor that promotes tumor cell immune escape and is a potential target for cancer diagnostic and immunotherapeutic applications. We used automated capillary electrophoresis (ACE), surface plasmon resonance (SPR), and immunohistochemistry (IHC) to compare the binding characteristics of a new anti-LAG3 rabbit antibody clone, SP464, with the thirty-year old and extensively used anti-LAG3 mouse 17B4 clone. The rabbit SP464 clone exhibited between 20× to 30× greater binding to LAG3 than did the mouse 17B4 clone. Using these tools, we precisely mapped the relative locations of the epitopes of these two antibodies. The SP464 and 17B4 minimal epitopes were localized to separate, but overlapping, sub-fragments within the amino-terminal fifteen acids of the original thirty-mer peptide immunogen used to generate both antibodies. Application of this approach for quantifying the effects of alanine substitutions along the minimal SP464 epitope identified two amino acids essential for binding and four amino acids that likely contribute towards binding. Together, ACE, SPR, and IHC constitute a powerful orthologous approach for comparing antibody-binding characteristics and for fine mapping of linear epitopes within short immunogens. Our results indicate that the rabbit clone SP464 may be useful for assessing LAG3 expression. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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13 pages, 2815 KiB  
Article
Development of a Novel Anti-EpCAM Monoclonal Antibody for Various Applications
by Guanjie Li, Hiroyuki Suzuki, Teizo Asano, Tomohiro Tanaka, Hiroyoshi Suzuki, Mika K. Kaneko and Yukinari Kato
Antibodies 2022, 11(2), 41; https://doi.org/10.3390/antib11020041 - 8 Jun 2022
Cited by 16 | Viewed by 4449
Abstract
The epithelial cell adhesion molecule (EpCAM) is a cell surface glycoprotein, which is widely expressed on normal and cancer cells. EpCAM is involved in cell adhesion, proliferation, survival, stemness, and tumorigenesis. Therefore, EpCAM is thought to be a promising target for cancer diagnosis [...] Read more.
The epithelial cell adhesion molecule (EpCAM) is a cell surface glycoprotein, which is widely expressed on normal and cancer cells. EpCAM is involved in cell adhesion, proliferation, survival, stemness, and tumorigenesis. Therefore, EpCAM is thought to be a promising target for cancer diagnosis and therapy. In this study, we established anti-EpCAM monoclonal antibodies (mAbs) using the Cell-Based Immunization and Screening (CBIS) method. We characterized them using flow cytometry, Western blotting, and immunohistochemistry. One of the established recombinant anti-EpCAM mAbs, recEpMab-37 (mouse IgG1, kappa), reacted with EpCAM-overexpressed Chinese hamster ovary-K1 cells (CHO/EpCAM) or a colorectal carcinoma cell line (Caco-2). In contrast, recEpMab-37 did not react with EpCAM-knocked out Caco-2 cells. The KD of recEpMab-37 for CHO/EpCAM and Caco-2 was 2.0 × 10−8 M and 3.2 × 10−8 M, respectively. We observed that EpCAM amino acids between 144 to 164 are involved in recEpMab-37 binding. In Western blot analysis, recEpMab-37 detected the EpCAM of CHO/EpCAM and Caco-2 cells. Furthermore, recEpMab-37 could stain formalin-fixed paraffin-embedded colorectal carcinoma tissues by immunohistochemistry. Taken together, recEpMab-37, established by the CBIS method, is useful for detecting EpCAM in various applications. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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17 pages, 5519 KiB  
Article
Discovering Novel Small Molecule Compound for Prevention of Monoclonal Antibody Self-Association
by Lok Hin Lui, Christopher F. van der Walle, Steve Brocchini and Ajoy Velayudhan
Antibodies 2022, 11(2), 40; https://doi.org/10.3390/antib11020040 - 8 Jun 2022
Cited by 2 | Viewed by 3836
Abstract
Designing an antibody with the desired affinity to the antigen is challenging, often achieved by lengthening the hydrophobic CDRs, which can lead to aggregation and cause major hindrance to the development of successful biopharmaceutical products. Aggregation can cause immunogenicity, viscosity and stability issues [...] Read more.
Designing an antibody with the desired affinity to the antigen is challenging, often achieved by lengthening the hydrophobic CDRs, which can lead to aggregation and cause major hindrance to the development of successful biopharmaceutical products. Aggregation can cause immunogenicity, viscosity and stability issues affecting both the safety and quality of the product. As the hydrophobic residues on the CDR are required for direct binding to antigens, it is not always possible to substitute these residues for aggregation-reduction purposes. Therefore, discovery of specific excipients to prevent aggregation is highly desirable for formulation development. Here, we used a combination of in silico screening methods to identify aggregation-prone regions on an aggregation-prone therapeutic antibody. The most aggregation-prone region on the antibody was selected to conduct virtual screening of compounds that can bind to such regions and act as an aggregation breaker. The most promising excipient candidate was further studied alongside plain buffer formulations and formulations with trehalose using coarse-grained molecular dynamics (CGMD) simulations with MARTINI force field. Mean interaction value between two antibody molecules in each formulation was calculated based on 1024 replicates of 512 ns of such CGMD simulations. Corresponding formulations with an excipient:antibody ratio of 1:5 were compared experimentally by measuring the diffusion interaction parameter kD and accelerated stability studies. Although the compound with the highest affinity score did not show any additional protective effects compared with trehalose, this study proved using a combination of in silico tools can aid excipient design and formulation development. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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10 pages, 1560 KiB  
Communication
Antibody Light Chains: Key to Increased Monoclonal Antibody Yields in Expi293 Cells?
by Siqi Gong, Seijal Gautam, Joshua D. Coneglio, Hanna B. Scinto and Ruth M. Ruprecht
Antibodies 2022, 11(2), 37; https://doi.org/10.3390/antib11020037 - 18 May 2022
Cited by 1 | Viewed by 4891
Abstract
When constructing isogenic recombinant IgM–IgG pairs, we discovered that μ heavy chains strongly prefer partnering with λ light chains for optimal IgM expression in transiently cotransfected Expi293 cells. When μ chains were paired with κ light chains, IgM yields were low but increased [...] Read more.
When constructing isogenic recombinant IgM–IgG pairs, we discovered that μ heavy chains strongly prefer partnering with λ light chains for optimal IgM expression in transiently cotransfected Expi293 cells. When μ chains were paired with κ light chains, IgM yields were low but increased by logs—up to 20,000 X—by using λ chains instead. Switching light chains did not alter epitope specificity. For dimeric IgA2, optimal expression involved pairing with λ chains, whereas light-chain preference varied for other immunoglobulin classes. In summary, recombinant IgM production can be drastically increased by using λ chains, an important finding in the use of IgM for mucosal immunoprophylaxis. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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19 pages, 3287 KiB  
Article
Effects of Monovalent Salt on Protein-Protein Interactions of Dilute and Concentrated Monoclonal Antibody Formulations
by Amy Y. Xu, Nicholas J. Clark, Joseph Pollastrini, Maribel Espinoza, Hyo-Jin Kim, Sekhar Kanapuram, Bruce Kerwin, Michael J. Treuheit, Susan Krueger, Arnold McAuley and Joseph E. Curtis
Antibodies 2022, 11(2), 24; https://doi.org/10.3390/antib11020024 - 31 Mar 2022
Cited by 9 | Viewed by 4682
Abstract
In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl (CNaCl) and monoclonal antibody (mAb) concentration (C [...] Read more.
In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl (CNaCl) and monoclonal antibody (mAb) concentration (CmAb) were assessed using the diffusion interaction parameter kD and second virial coefficient B22 measured from solutions with low to moderate CmAb. The effective structure factor S(q)eff measured from concentrated mAb solutions using small-angle X-ray and neutron scattering (SAXS/SANS) was also used to characterize the PPI. Our results found that the nature of net PPI changed not only with CNaCl, but also with increasing CmAb. As a result, parameters measured from dilute and concentrated mAb samples could lead to different predictions on the stability of mAb formulations. We also compared experimentally determined viscosity results with those predicted from interaction parameters, including kD and S(q)eff. The lack of a clear correlation between interaction parameters and measured viscosity values indicates that the relationship between viscosity and PPI is concentration-dependent. Collectively, the behavior of flexible mAb molecules in concentrated solutions may not be correctly predicted using models where proteins are considered to be uniform colloid particles defined by parameters derived from low CmAb. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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43 pages, 4424 KiB  
Article
Ramifications of the HLA-I Allelic Reactivity of Anti-HLA-E*01:01 and Anti-HLA-E*01:03 Heavy Chain Monoclonal Antibodies in Comparison with Anti-HLA-I IgG Reactivity in Non-Alloimmunized Males, Melanoma-Vaccine Recipients, and End-Stage Renal Disease Patients
by Mepur H. Ravindranath, Narendranath M. Ravindranath, Fatiha El Hilali, Senthamil R. Selvan and Edward J. Filippone
Antibodies 2022, 11(1), 18; https://doi.org/10.3390/antib11010018 - 2 Mar 2022
Cited by 5 | Viewed by 3489
Abstract
Serum anti-HLA-I IgG are present in non-alloimmunized males, cancer patients, and transplant recipients. Anti-HLA-I antibodies are also present in intravenous immunoglobulin (IVIg), prepared from the plasma of thousands of healthy donors. However, the HLA-Ia reactivity of IVIg diminishes markedly after passing through HLA-E [...] Read more.
Serum anti-HLA-I IgG are present in non-alloimmunized males, cancer patients, and transplant recipients. Anti-HLA-I antibodies are also present in intravenous immunoglobulin (IVIg), prepared from the plasma of thousands of healthy donors. However, the HLA-Ia reactivity of IVIg diminishes markedly after passing through HLA-E HC-affinity columns, suggesting that the HLA-I reactivity is due to antibodies formed against HLA-E. Hence, we examined whether anti-HLA-E antibodies can react to HLA-I alleles. Monoclonal IgG antibodies (mAbs) against HCs of two HLA-E alleles were generated in Balb/C mice. The antibodies were analyzed using multiplex bead assays on a Luminex platform for HLA-I reactivity. Beads coated with an array of HLA heterodimers admixed with HCs (LABScreen) were used to examine the binding of IgG to different HLA-Ia (31-HLA-A, 50-HLA-B, and 16-HLA-C) and Ib (2-HLA-E, one each of HLA-F and HLA-G) alleles. A striking diversity in the HLA-Ia and/or HLA-Ib reactivity of mAbs was observed. The number of the mAbs reactive to (1) only HLA-E (n = 25); (2) all HLA-Ib isomers (n = 8); (3) HLA-E and HLA-B (n = 5); (4) HLA-E, HLA-B, and HLA-C (n = 30); (5) HLA-E, HLA-A*1101, HLA-B, and HLA-C (n = 83); (6) HLA-E, HLA-A, HLA-B, and HLA-C (n = 54); and (7) HLA-Ib and HLA-Ia (n = 8), in addition to four other minor groups. Monospecificity and polyreactivity were corroborated by HLA-E monospecific and HLA-I shared sequences. The diverse HLA-I reactivity of the mAbs are compared with the pattern of HLA-I reactivity of serum-IgG in non-alloimmunized males, cancer patients, and ESKD patients. The findings unravel the diagnostic potential of the HLA-E monospecific-mAbs and immunomodulatory potentials of IVIg highly mimicking HLA-I polyreactive-mAbs. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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14 pages, 2288 KiB  
Article
Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
by Dennis R. Goulet, Soumili Chatterjee, Wai-Ping Lee, Andrew B. Waight, Yi Zhu and Amanda Nga-Sze Mak
Antibodies 2022, 11(1), 6; https://doi.org/10.3390/antib11010006 - 13 Jan 2022
Cited by 9 | Viewed by 5550
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers [...] Read more.
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers such as colorectal cancer and head and neck cancer. Cetuximab is a chimeric monoclonal antibody containing mouse variable regions that bind to EGFR and prevent it from signaling. Although cetuximab has been used clinically since 2004 to successfully control solid tumors, advances in protein engineering have created the opportunity to address some of its shortcomings. In particular, the presence of mouse sequences could contribute to immunogenicity in the form of anti-cetuximab antibodies, and an occupied glycosylation site in FR3 can contribute to hypersensitivity reactions and product heterogeneity. Using simple framework graft or sequence-/structure-guided approaches, cetuximab was humanized onto 11 new frameworks. In addition to increasing humanness and removing the VH glycosylation site, dynamic light scattering revealed increases in stability, and bio-layer interferometry confirmed minimal changes in binding affinity, with patterns emerging across the humanization method. This work demonstrates the potential to improve the biophysical and clinical properties of first-generation protein therapeutics and highlights the advantages of computationally guided engineering. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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16 pages, 2499 KiB  
Article
Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules
by Amita Datta-Mannan, Robin Brown, Stephanie Key, Paul Cain and Yiqing Feng
Antibodies 2022, 11(1), 2; https://doi.org/10.3390/antib11010002 - 28 Dec 2021
Cited by 8 | Viewed by 5507
Abstract
Bispecific antibodies (BsAb) that engage multiple pathways are a promising therapeutic strategy to improve and prolong the efficacy of biologics in complex diseases. In the early stages of discovery, BsAbs often exhibit a broad range of pharmacokinetic (PK) behavior. Optimization of the neonatal [...] Read more.
Bispecific antibodies (BsAb) that engage multiple pathways are a promising therapeutic strategy to improve and prolong the efficacy of biologics in complex diseases. In the early stages of discovery, BsAbs often exhibit a broad range of pharmacokinetic (PK) behavior. Optimization of the neonatal Fc receptor (FcRn) interactions and removal of undesirable physiochemical properties have been used to improve the ‘pharmacokinetic developability’ for various monoclonal antibody (mAb) therapeutics, yet there is a sparsity of such information for BsAbs. The present work evaluated the influence of FcRn interactions and inherent physiochemical properties on the PK of two related single chain variable fragment (scFv)-based BsAbs. Despite their close relation, the two BsAbs exhibit disparate PK in cynomolgus monkeys with BsAb-1 having an aberrant clearance of ~2 mL/h/kg and BsAb-2 displaying a an ~10-fold slower clearance (~0.2 mL/h/kg). Evaluation of the physiochemical characteristics of the molecules, including charge, non-specific binding, thermal stability, and hydrophobic properties, as well as FcRn interactions showed some differences. In-depth drug disposition results revealed that a substantial disparity in the complete release from FcRn at a neutral pH is a primary factor contributing to the rapid clearance of the BsAb-1 while other biophysical characteristics were largely comparable between molecules. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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Review

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17 pages, 8390 KiB  
Review
A New Method to Characterize Conformation-Specific Antibody by a Combination of Agarose Native Gel Electrophoresis and Contact Blotting
by Teruo Akuta, Toshiaki Maruyama, Chiaki Sakuma, Masataka Nakagawa, Yui Tomioka, Kevin Entzminger, Jonathan K. Fleming, Ryo Sato, Takashi Shibata, Yasunori Kurosawa, C. J. Okumura and Tsutomu Arakawa
Antibodies 2022, 11(2), 36; https://doi.org/10.3390/antib11020036 - 12 May 2022
Cited by 8 | Viewed by 8956
Abstract
In this study, we review the agarose native gel electrophoresis that separates proteins and macromolecular complexes in their native state and transfer of the separated proteins from the agarose gel to membranes by contact blotting which retains the native state of these structures. [...] Read more.
In this study, we review the agarose native gel electrophoresis that separates proteins and macromolecular complexes in their native state and transfer of the separated proteins from the agarose gel to membranes by contact blotting which retains the native state of these structures. Green fluorescent protein showed functional state both on agarose gel and blotted membrane. Based on the combined procedures, we discovered conformation-specific monoclonal antibodies against PLXDC2 and SARS-CoV-2 spike protein. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)
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