Review
Oncology
Ilana Schlam, Ruth Moges, Stefania Morganti, Sara M. Tolaney, Paolo Tarantino
Summary: Antibody-drug conjugates (ADCs) have revolutionized the treatment of different types of breast cancer, with several ADCs approved for each subtype. The components of ADCs, including the antibody, linker, and payload, have a significant impact on their efficacy and toxicity profile, and modifications can lead to major changes in their clinical characteristics. Novel ADCs are currently being investigated, with approaches such as targeting different antigens, exploring innovative constructs, and incorporating dual payloads or immune-modulating properties. This review article discusses the evolving landscape of novel ADCs and the challenges and opportunities in this field.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2023)
Editorial Material
Chemistry, Medicinal
Jerome H. Hochman
Summary: The development of multiple drug modalities in the past 20 years has expanded the therapeutic space for intervention in disease processes. These modalities are complementary in target space and biological mechanisms. Successful application of novel therapeutics requires understanding physiological, biochemical, and biological barriers, as well as unique attributes and potential off-target biological responses.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemical Research Methods
Magnus Palmblad
Summary: Future single-molecule sequencing technologies focus on sequencing individual peptides or protein molecules to uniquely identify human proteins based on the number and types of amino acids. Simulation results suggest that the optimal choice of reading N amino acids performs similarly to the average choice of N+1 amino acids, and the discrimination power of amino acids scales with their frequency in the proteome.
JOURNAL OF PROTEOME RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Xinrong Yang, Yiming Shao, Shanshan Wang, Mingxia Chen, Bo Xiao, Rui Sun, Jie Min
Summary: The development of organic semiconductors has improved the efficiency, stability, and cost of organic photovoltaic devices. However, there is still a need to enhance the processability of these materials. This article reviews methods to improve the processability of organic photovoltaic materials and proposes a comprehensive set of key performance indicators to evaluate processability.
ADVANCED MATERIALS
(2023)
Article
Pharmacology & Pharmacy
Kai H. Liao, Jason H. Williams, Santhosh Palani, Donghua Yin, Xu Meng
Summary: This study describes the use of three joint disposition metrics (JDMs) for integrated pharmacokinetic (PK) analysis of antibody-drug conjugates (ADCs). These JDMs offer an effective approach for comparing ADCs in terms of favorable PK characteristics by comparing the ratio of appropriate PK parameters of ADC components, and their utility is demonstrated in both clinical candidates and FDA-approved ADCs.
Review
Clinical Neurology
Tobias Ruck, Falk Nimmerjahn, Heinz Wiendl, Jan D. Luenemann
Summary: Ruck et al. provide an overview of advancements in next-generation antibody-based therapies for brain diseases, focusing on Fc engineering and improving bioavailability in the CNS parenchyma. They discuss the potential benefits and limitations of these therapies in neurology. Antibody-based treatments have become standard in neuroinflammatory diseases, and efforts are being made to expand their use to a wider range of neurological disorders. The specificity and effectiveness of these treatments are determined by engineering the antigen-binding fragment (Fab) and the crystallizable fragment (Fc) of the antibodies. The development of technologies to enhance the bioavailability of these treatments within the brain shows promise for improving options for patients with limited therapeutic choices.
Article
Immunology
Ran Salomon, Rony Dahan
Summary: The clinical use of anti-CD40 agonist monoclonal antibodies faces challenges due to dose-limiting toxicity. Novel approaches are being explored to overcome the systemic toxicity associated with CD40 agonism.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Chemistry, Medicinal
Karoline Bechtold-Peters, Andrea Ruggiero, Nienke Vriezen, Nathan Ihle, Armin Klein, Charles Morgan, Daniel Schweizer, Dengfeng Liu, Fred Jacobson, Jakob Buecheler, Mark Panek, Naomi Duggan, Padma Malyala, Philippe Dupraz, Priyanka Desai, Shufang Niu, Yiqing Feng, Xiangyang Wang
Summary: Antibody-drug conjugates combine the specificity and long circulation time of an antibody with the toxicity of a chemical drug, resulting in an increase in complexity. Multiple production processes are required to produce the components and form the final antibody-drug conjugate. By combining scientific understanding and risk-based approaches, quality can be demonstrated and redundant studies can be avoided. The structure of the module 3 common technical document for an ADC needs to reflect each production process and the overall approach to quality.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Jonathan Schwach, Mustafa Abdellatif, Andreas Stengl
Summary: ADCs have become a cornerstone in targeted cancer therapies, with rapid development of novel conjugation techniques and alternative payloads. Multi-specific antibody formats show great potential for the next generation of therapeutic antibody conjugates.
FRONTIERS IN BIOSCIENCE-LANDMARK
(2022)
Review
Pharmacology & Pharmacy
William R. Lykins, Christopher B. Fox
Summary: In recent years, there has been increased interest in vaccine adjuvant development for new and emerging vaccine modalities. However, the development of vaccine adjuvants still faces challenges, including translation complexities, safety concerns, and sourcing raw materials at scale. This review explores various adjuvant technologies and provides recommendations for improving clinical success through early consideration of factors and application of tools in the vaccine development pipeline.
Article
Biochemistry & Molecular Biology
Hye Lim Choi, Ha Rim Yang, Ha Gyeong Shin, Kyusang Hwang, Ji Woong Kim, Ji Hyun Lee, Taehoon Ryu, Yushin Jung, Sukmook Lee
Summary: Antibody phage display is a crucial technology for discovering and developing target-specific monoclonal antibodies. This study constructed a large human combinatorial single-chain variable fragment library with high diversity, which can be used for the rapid development of recombinant human monoclonal antibodies for therapeutic and diagnostic applications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Ian Nessler, Bruna Menezes, Greg M. Thurber
Summary: Despite the recent FDA approval of six new ADCs, the attrition rate of ADCs during clinical development remains high. ADC design influences their pharmacokinetics and pharmacodynamics, requiring in-depth analysis for clinical dosing.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Oncology
Guang Wu, Lan Li, Mengnan Liu, Chunyan Chen, Guangze Wang, Zewei Jiang, Yaqian Qin, Licai He, Hongzhi Li, Jiawei Cao, Haihua Gu
Summary: The generated HzMUC1-ADC demonstrated promising targeted therapy potential for pancreatic cancer, as it inhibited tumor cell growth, induced apoptosis, and significantly reduced xenograft tumor growth in vivo.
CANCER CELL INTERNATIONAL
(2022)
Review
Medicine, General & Internal
Andrea D'Arienzo, Annarita Verrazzo, Martina Pagliuca, Fabiana Napolitano, Sara Parola, Martina Viggiani, Roberta Caputo, Fabio Puglisi, Mario Giuliano, Lucia Del Mastro, Grazia Arpino, Michelino De Laurentiis, Filippo Montemurro
Summary: Antibody-drug conjugates (ADCs) are a new and evolving class of antineoplastic agents that deliver cytotoxic compounds at the tumor site, reducing systemic exposure and toxicity. Although generally well tolerated, they can cause predictable adverse reactions such as neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, and ILD/pneumonitis. This review provides updated evidence on the toxicities of ADCs used in breast cancer treatment and proposes monitoring protocols and clinical management strategies to prevent or promptly address these problems.
Article
Medicine, Research & Experimental
Min Ji Ko, Daehae Song, Juhee Kim, Jae Yong Kim, Jaehyun Eom, Byungje Sung, Yong-Gyu Son, Young Min Kim, Sang Hoon Lee, Weon-Kyoo You, Jinwon Jung
Summary: The new type of ADC (NTERM conjugation) reduces toxicity while maintaining efficacy through a more stable conjugation method; indicating that the NTERM conjugation method could widen the therapeutic window of ADCs by enhancing stability and reducing toxicity.
Review
Pharmacology & Pharmacy
Imke H. Bartelink, Ella F. Jones, Sheerin K. Shahidi-Latham, Pei Rong Evelyn Lee, Yanan Zheng, Paolo Vicini, Laura van't Veer, Denise Wolf, Andrei Iagaru, Deanna L. Kroetz, Brendan Prideaux, Cornelius Cilliers, Greg M. Thurber, Zena Wimana, Geraldine Gebhart
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2019)
Article
Chemistry, Multidisciplinary
Tejas Navaratna, Lydia Atangcho, Mukesh Mahajan, Vivekanandan Subramanian, Marshall Case, Andrew Min, Daniel Tresnak, Greg M. Thurber
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2020)
Article
Pharmacology & Pharmacy
Ian Nessler, Cornelius Cilliers, Greg M. Thurber
Letter
Radiology, Nuclear Medicine & Medical Imaging
Greg M. Thurber
JOURNAL OF NUCLEAR MEDICINE
(2021)
Article
Oncology
Eshita Khera, Cornelius Cilliers, Michael D. Smith, Michelle L. Ganno, Katharine C. Lai, Thomas A. Keating, Anna Kopp, Ian Nessler, Adnan O. Abu-Yousif, Greg M. Thurber
Summary: Three newly approved ADCs have been found to exhibit bystander effects, where the drug payload can diffuse into adjacent cells, providing potential benefits for targeted cancer treatment. However, the extent of diffusion in tumor tissue and its impact on treatment efficacy remains unclear, highlighting the need for further research in this area.
Article
Pharmacology & Pharmacy
Bruna Menezes, Jennifer J. Linderman, Greg M. Thurber
Summary: Intratumoral heterogeneity is a significant factor in tumor recurrence. Combination therapy has shown potential in improving treatment efficacy, but its effectiveness may be hindered by heterogeneity in tumor distribution and drug efficacy. Thus, alternative treatment mechanisms need to be explored for durable treatment responses.
DRUG METABOLISM AND DISPOSITION
(2022)
Review
Pharmacology & Pharmacy
Ian Nessler, Bruna Menezes, Greg M. Thurber
Summary: Despite the recent FDA approval of six new ADCs, the attrition rate of ADCs during clinical development remains high. ADC design influences their pharmacokinetics and pharmacodynamics, requiring in-depth analysis for clinical dosing.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Oncology
Anna Kopp, Scott Hofsess, Thomas M. Cardillo, Serengulam Govindan, Jennifer Donnell, Greg M. Thurber
Summary: Antibody-drug conjugates (ADCs) are a rapidly growing class of targeted cancer treatments. This study focused on sacituzumab govitecan (SG; Trodelvy), which is a recently approved ADC, to understand its efficacy. The researchers used a quantitative pharmacokinetic approach to study the distribution and mechanisms of SG in a gastric cancer model. They found that SG exhibited efficient tumor penetration and intracellular linker cleavage, leading to increased efficacy. This study provides valuable insights for the design of future ADCs and prodrugs.
MOLECULAR CANCER THERAPEUTICS
(2023)
Article
Biochemical Research Methods
Laureen de Bever, Sorraya Popal, Jord van Schaik, Baron Rubahamya, Floris L. van Delft, Greg M. Thurber, Sander S. van Berkel
Summary: GlycoConnect technology is adaptable for different drug-to-antibody ratios (DARs) and is being evaluated in clinical programs. Ultrapotent payloads in ADCs can only be administered at low doses, compromising effective biodistribution and target receptor saturation. This study demonstrates that GlycoConnect technology can be extended to DAR1 ADCs without antibody reengineering and shows the potential of a lower DAR for ADCs with ultrapotent payloads through improved tumor penetration.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Eshita Khera, Jaeyeon Kim, Andrew Stein, Matt Ratanapanichkich, Greg M. Thurber
Summary: The measurement of receptor occupancy in clinical settings is challenging, especially for solid tumors. Mathematical models are used to predict tumor receptor occupancy and guide dose decisions. A new metric called average free tissue target to initial target ratio (AFTIR) has been developed to predict receptor occupancy at near-saturating dose regimens. However, this metric fails to accurately predict receptor occupancy at clinically relevant subsaturating antibody doses. In this study, a partial differential equation (PDE) Krogh cylinder model is used to simulate spatiotemporal receptor occupancy and derive an analytical solution, called mechanistically weighted global AFTIR, that can better predict receptor occupancy regardless of dosing regimen. The inclusion of a new parameter, absolute receptor density, improves the accuracy of the metric. This generalized AFTIR serves as a more accurate analytical tool for clinical dose decisions and rational design of antibody-based therapeutics without the need for extensive PDE simulations.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Eshita Khera, Jaeyeon Kim, Andrew Stein, Matt Ratanapanichkich, Greg M. Thurber
Summary: This study presents a mathematically rigorous but simplified analytical model to accurately predict receptor occupancy across a range of affinities, doses, drug, and tumor properties. The importance of this research lies in providing an effective prediction tool for dose decisions in pharmaceutical development, without the need for complex computer simulations.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Article
Multidisciplinary Sciences
Guolan Lu, Naoki Nishio, Nynke S. van den Berg, Brock A. Martin, Shayan Fakurnejad, Stan van Keulen, Alexander D. Colevas, Greg M. Thurber, Eben L. Rosenthal
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Sumit Bhatnagar, Eshita Khera, Jianshan Liao, Victoria Eniola, Yongjun Hu, David E. Smith, Greg M. Thurber
SCIENTIFIC REPORTS
(2019)
Article
Chemistry, Physical
Eshita Khera, Cornelius Cilliers, Sumit Bhatnagar, Greg M. Thurber
MOLECULAR SYSTEMS DESIGN & ENGINEERING
(2018)
Article
Oncology
Cornelius Cilliers, Bruna Menezes, Ian Nessler, Jennifer Linderman, Greg M. Thurber