International Journal of Molecular Sciences

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Open AccessEditorial

Recent Advances in Antibody Therapeutics

by Yong-Seok Heo

Int. J. Mol. Sci. 2022, 23(7), 3690; https://doi.org/10.3390/ijms23073690 - 28 Mar 2022

Cited by 5 | Viewed by 2288

Abstract

Antibody-based therapeutics have achieved unprecedented success in treating various diseases, including cancers, immune disorders, and infectious diseases [...] Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

Research

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15 pages, 2292 KiB

Open AccessArticle

Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods

by Heesu Chae, Seulki Cho, Munsik Jeong, Kiyoung Kwon, Dongwook Choi, Jaeyoung Lee, Woosuk Nam, Jisu Hong, Jiwoo Lee, Seonjoo Yoon and Hyojeong Hong

Int. J. Mol. Sci. 2021, 22(13), 6696; https://doi.org/10.3390/ijms22136696 - 22 Jun 2021

Cited by 2 | Viewed by 3185

Abstract

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity [...] Read more.

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)—which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue—exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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12 pages, 2538 KiB

Open AccessArticle

Affinity Maturation of a T-Cell Receptor-Like Antibody Specific for a Cytomegalovirus pp65-Derived Peptide Presented by HLA-A*02:01

by Se-Young Lee, Deok-Han Ko, Min-Jeong Son, Jeong-Ah Kim, Keunok Jung and Yong-Sung Kim

Int. J. Mol. Sci. 2021, 22(5), 2349; https://doi.org/10.3390/ijms22052349 - 26 Feb 2021

Cited by 7 | Viewed by 3305

Abstract

Human cytomegalovirus (CMV) infection is widespread among adults (60–90%) and is usually undetected in healthy individuals without symptoms but can cause severe diseases in immunocompromised hosts. T-cell receptor (TCR)-like antibodies (Abs), which recognize complex antigens (peptide–MHC complex, pMHC) composed of MHC molecules with [...] Read more.

Human cytomegalovirus (CMV) infection is widespread among adults (60–90%) and is usually undetected in healthy individuals without symptoms but can cause severe diseases in immunocompromised hosts. T-cell receptor (TCR)-like antibodies (Abs), which recognize complex antigens (peptide–MHC complex, pMHC) composed of MHC molecules with embedded short peptides derived from intracellular proteins, including pathogenic viral proteins, can serve as diagnostic and/or therapeutic agents. In this study, we aimed to engineer a TCR-like Ab specific for pMHC comprising a CMV pp65 protein-derived peptide (⁴⁹⁵NLVPMVATV⁵⁰³; hereafter, CMVpp65_495-503) in complex with MHC-I molecule human leukocyte antigen (HLA)-A*02:01 (CMVpp65_495-503/HLA-A*02:01) to increase affinity by sequential mutagenesis of complementarity-determining regions using yeast surface display technology. Compared with the parental Ab, the final generated Ab (C1-17) showed ~67-fold enhanced binding affinity (K_D ≈ 5.2 nM) for the soluble pMHC, thereby detecting the cell surface-displayed CMVpp65_495-503/HLA-A*02:01 complex with high sensitivity and exquisite specificity. Thus, the new high-affinity TCR-like Ab may be used for the detection and treatment of CMV infection. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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18 pages, 1493 KiB

Open AccessArticle

Neutralizing Human Antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 Isolated from a Human Synthetic Fab Phage Display Library

by Yu Jung Kim, Min Ho Lee, Se-Ra Lee, Hyo-Young Chung, Kwangmin Kim, Tae Gyu Lee and Dae Young Kim

Int. J. Mol. Sci. 2021, 22(4), 1913; https://doi.org/10.3390/ijms22041913 - 15 Feb 2021

Cited by 13 | Viewed by 3935

Abstract

Since it was first reported in Wuhan, China, in 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic outbreak resulting in a tremendous global threat due to its unprecedented rapid spread and an absence of a prophylactic vaccine or [...] Read more.

Since it was first reported in Wuhan, China, in 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic outbreak resulting in a tremendous global threat due to its unprecedented rapid spread and an absence of a prophylactic vaccine or therapeutic drugs treating the virus. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is a key player in the viral entry into cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor protein, and the RBD has therefore been crucial as a drug target. In this study, we used phage display to develop human monoclonal antibodies (mAbs) that neutralize SARS-CoV-2. A human synthetic Fab phage display library was panned against the RBD of the SARS-CoV-2 spike protein (SARS-2 RBD), yielding ten unique Fabs with moderate apparent affinities (EC₅₀ = 19–663 nM) for the SARS-2 RBD. All of the Fabs showed no cross-reactivity to the MERS-CoV spike protein, while three Fabs cross-reacted with the SARS-CoV spike protein. Five Fabs showed neutralizing activities in in vitro assays based on the Fabs’ activities antagonizing the interaction between the SARS-2 RBD and ACE2. Reformatting the five Fabs into immunoglobulin Gs (IgGs) greatly increased their apparent affinities (K_D = 0.08–1.0 nM), presumably due to the effects of avidity, without compromising their non-aggregating properties and thermal stability. Furthermore, two of the mAbs (D12 and C2) significantly showed neutralizing activities on pseudo-typed and authentic SARS-CoV-2. Given their desirable properties and neutralizing activities, we anticipate that these human anti-SARS-CoV-2 mAbs would be suitable reagents to be further developed as antibody therapeutics to treat COVID-19, as well as for diagnostics and research tools. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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14 pages, 2177 KiB

Open AccessArticle

ABL001, a Bispecific Antibody Targeting VEGF and DLL4, with Chemotherapy, Synergistically Inhibits Tumor Progression in Xenograft Models

by Dong-Hoon Yeom, Yo-Seob Lee, Ilhwan Ryu, Sunju Lee, Byungje Sung, Han-Byul Lee, Dongin Kim, Jin-Hyung Ahn, Eunsin Ha, Yong-Soo Choi, Sang Hoon Lee and Weon-Kyoo You

Int. J. Mol. Sci. 2021, 22(1), 241; https://doi.org/10.3390/ijms22010241 - 29 Dec 2020

Cited by 26 | Viewed by 6024

Abstract

Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 [...] Read more.

Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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13 pages, 1874 KiB

Open AccessArticle

Blocking of the IL-33/ST2 Signaling Axis by a Single-Chain Antibody Variable Fragment (scFv) Specific to IL-33 with a Defined Epitope

by Soo Bin Park, Sun-Jick Kim, Sang Woo Cho, Cheol Yong Choi and Sangho Lee

Int. J. Mol. Sci. 2020, 21(18), 6953; https://doi.org/10.3390/ijms21186953 - 22 Sep 2020

Cited by 6 | Viewed by 3740

Abstract

Interleukin 33 (IL-33) is an IL-1 family cytokine that plays a central role in immune system by regulating and initiating inflammatory responses. The binding of IL-33 to the suppressor of tumorigenicity 2 (ST2) receptor induces mitogen-activated protein kinases (MAPK) and nuclear factor κB [...] Read more.

Interleukin 33 (IL-33) is an IL-1 family cytokine that plays a central role in immune system by regulating and initiating inflammatory responses. The binding of IL-33 to the suppressor of tumorigenicity 2 (ST2) receptor induces mitogen-activated protein kinases (MAPK) and nuclear factor κB (NF-κB) pathways, thereby leading to inflammatory cytokines production in type 2 helper T cells and type 2 innate lymphoid cells. To develop an antibody specific to IL-33 with a defined epitope, we characterized a single-chain antibody variable fragments (scFvs) clone specific to IL-33, C2_2E12, which was selected from a human synthetic library of scFvs using phage display. Affinity (K_d) of C2_2E12 was determined to be 38 nM using enzyme-linked immunosorbent assay. C2_2E12 did not show cross-reactivity toward other interleukin cytokines, including closely related IL-1 family cytokines and unrelated proteins. Mutational scanning analysis revealed that the epitope of IL-33 consisted of residues 149–158 with key residues being L150 and K151 of IL-33. Structural modeling suggested that L150 and K151 residues are important for the interaction of IL-33 with C2_2E12, implicating that C2_2E12 could block the binding of ST2 to IL-33. Pull-down and in-cell assays supported that C2_2E12 can inhibit the IL-33/ST2 signaling axis. These results suggest that the scFv clone characterized here can function as a neutralizing antibody. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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Review

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16 pages, 17169 KiB

Open AccessReview

Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

by Yuko Abe, Yasuhiko Suga, Kiyoharu Fukushima, Hayase Ohata, Takayuki Niitsu, Hiroshi Nabeshima, Yasuharu Nagahama, Hiroshi Kida and Atsushi Kumanogoh

Int. J. Mol. Sci. 2022, 23(1), 83; https://doi.org/10.3390/ijms23010083 - 22 Dec 2021

Cited by 8 | Viewed by 5033

Abstract

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. [...] Read more.

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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22 pages, 3079 KiB

Open AccessReview

Targeting Human Papillomavirus-Associated Cancer by Oncoprotein-Specific Recombinant Antibodies

by Maria Gabriella Donà, Paola Di Bonito, Maria Vincenza Chiantore, Carla Amici and Luisa Accardi

Int. J. Mol. Sci. 2021, 22(17), 9143; https://doi.org/10.3390/ijms22179143 - 24 Aug 2021

Cited by 4 | Viewed by 3242

Abstract

In recent decades, recombinant antibodies against specific antigens have shown great promise for the therapy of infectious diseases and cancer. Human papillomaviruses (HPVs) are involved in the development of around 5% of all human cancers and HPV16 is the high-risk genotype with the [...] Read more.

In recent decades, recombinant antibodies against specific antigens have shown great promise for the therapy of infectious diseases and cancer. Human papillomaviruses (HPVs) are involved in the development of around 5% of all human cancers and HPV16 is the high-risk genotype with the highest prevalence worldwide, playing a dominant role in all HPV-associated cancers. Here, we describe the main biological activities of the HPV16 E6, E7, and E5 oncoproteins, which are involved in the subversion of important regulatory pathways directly associated with all known hallmarks of cancer. We then review the state of art of the recombinant antibodies targeted to HPV oncoproteins developed so far in different formats, and outline their mechanisms of action. We describe the advantages of a possible antibody-based therapy against the HPV-associated lesions and discuss the critical issue of delivery to tumour cells, which must be addressed in order to achieve the desired translation of the antibodies from the laboratory to the clinic. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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24 pages, 2682 KiB

Open AccessReview

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

by Aida Kouhi, Vyshnavi Pachipulusu, Talya Kapenstein, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli

Int. J. Mol. Sci. 2021, 22(12), 6442; https://doi.org/10.3390/ijms22126442 - 16 Jun 2021

Cited by 56 | Viewed by 5974

Abstract

Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has [...] Read more.

Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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16 pages, 975 KiB

Open AccessReview

Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

by Eunhye Ji and Sahmin Lee

Int. J. Mol. Sci. 2021, 22(11), 5770; https://doi.org/10.3390/ijms22115770 - 28 May 2021

Cited by 43 | Viewed by 10411

Abstract

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as [...] Read more.

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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20 pages, 1413 KiB

Open AccessReview

Bioassay Development for Bispecific Antibodies—Challenges and Opportunities

by Ames C. Register, Somayeh S. Tarighat and Ho Young Lee

Int. J. Mol. Sci. 2021, 22(10), 5350; https://doi.org/10.3390/ijms22105350 - 19 May 2021

Cited by 15 | Viewed by 7534

Abstract

Antibody therapeutics are expanding with promising clinical outcomes, and diverse formats of antibodies are further developed and available for patients of the most challenging disease areas. Bispecific antibodies (BsAbs) have several significant advantages over monospecific antibodies by engaging two antigen targets. Due to [...] Read more.

Antibody therapeutics are expanding with promising clinical outcomes, and diverse formats of antibodies are further developed and available for patients of the most challenging disease areas. Bispecific antibodies (BsAbs) have several significant advantages over monospecific antibodies by engaging two antigen targets. Due to the complicated mechanism of action, diverse structural variations, and dual-target binding, developing bioassays and other types of assays to characterize BsAbs is challenging. Developing bioassays for BsAbs requires a good understanding of the mechanism of action of the molecule, principles and applications of different bioanalytical methods, and phase-appropriate considerations per regulatory guidelines. Here, we review recent advances and case studies to provide strategies and insights for bioassay development for different types of bispecific molecules. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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11 pages, 1058 KiB

Open AccessReview

Antibody Libraries as Tools to Discover Functional Antibodies and Receptor Pleiotropism

by Chih-Wei Lin and Richard A. Lerner

Int. J. Mol. Sci. 2021, 22(8), 4123; https://doi.org/10.3390/ijms22084123 - 16 Apr 2021

Cited by 9 | Viewed by 3558

Abstract

Most antibodies currently in use have been selected based on their binding affinity. However, nowadays, antibodies that can not only bind but can also alter the function of cell surface signaling components are increasingly sought after as therapeutic drugs. Therefore, the identification of [...] Read more.

Most antibodies currently in use have been selected based on their binding affinity. However, nowadays, antibodies that can not only bind but can also alter the function of cell surface signaling components are increasingly sought after as therapeutic drugs. Therefore, the identification of such functional antibodies from a large antibody library is the subject of intensive research. New methods applied to combinatorial antibody libraries now allow the isolation of functional antibodies in the cellular environment. These selected agonist antibodies have provided new insights into important issues of signal transduction. Notably, when certain antibodies bind to a given receptor, the cell fate induced by them may be the same or different from that induced by natural agonists. In addition, combined with phenotypic screening, this platform allows us to discover unexpected experimental results and explore various phenomena in cell biology, such as those associated with stem cells and cancer cells. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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14 pages, 2339 KiB

Open AccessReview

Antigen Design for Successful Isolation of Highly Challenging Therapeutic Anti-GPCR Antibodies

by Man-Seok Ju and Sang Taek Jung

Int. J. Mol. Sci. 2020, 21(21), 8240; https://doi.org/10.3390/ijms21218240 - 3 Nov 2020

Cited by 11 | Viewed by 9009

Abstract

G-protein-coupled receptors (GPCR) transmit extracellular signals into cells to regulate a variety of cellular functions and are closely related to the homeostasis of the human body and the progression of various types of diseases. Great attention has been paid to GPCRs as excellent [...] Read more.

G-protein-coupled receptors (GPCR) transmit extracellular signals into cells to regulate a variety of cellular functions and are closely related to the homeostasis of the human body and the progression of various types of diseases. Great attention has been paid to GPCRs as excellent drug targets, and there are many commercially available small-molecule chemical drugs against GPCRs. Despite this, the development of therapeutic anti-GPCR antibodies has been delayed and is challenging due to the difficulty in preparing active forms of GPCR antigens, resulting from their low cellular expression and complex structures. Here, we focus on anti-GPCR antibodies that have been approved or are subject to clinical trials and present various technologies to prepare active GPCR antigens that enable the isolation of therapeutic antibodies to proceed toward clinical validation. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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25 pages, 635 KiB

Open AccessReview

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

by Olga Bednova and Jeffrey V. Leyton

Int. J. Mol. Sci. 2020, 21(19), 7268; https://doi.org/10.3390/ijms21197268 - 1 Oct 2020

Cited by 36 | Viewed by 5302

Abstract

The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can [...] Read more.

The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment. Full article

(This article belongs to the Special Issue Recent Advances in Antibody Therapeutics)

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