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Strategies and Challenges for the Next Generation of Antibody Drug...
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Strategies and Challenges for the Next Generation of Antibody Drug Conjugates

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 30191

Special Issue Editor

Dr. Jagath Reddy Junutula

E-Mail Website
Guest Editor
Research & Development, ModMab Therapeutics, Inc., Foster City, CA, USA
Interests: antibody therapeutics; antibody-drug conjugates; bi-specific antibodies; cancer drug discovery; targeted chemotherapy; cancer immunotherapy

Special Issue Information

Dear Colleagues:

Antibody-drug conjugates (ADCs) are designed to selectively deliver a cytotoxic payload to the cancer cell. There are now  seven approved ADCs for the treatment of several different cancers and ~80 ADCs in clinical development with over 600 clinical trials, which highlights the exponential growth for this important therapeutic landscape. Past 10 years, ADC field has been witnessing significant technology improvements with respect to ADC target selection, payload diversity, linker design, site-specific conjugation technology and application of clinical and translational strategies in developing next generation ADCs. In this special issue, we like to highlight many such pre-clinical, translational and clinical findings to improve therapeutic index of this novel ADC therapeutic platform, thus by making paradigm shift in cancer chemotherapy.

Dr. Jagath Reddy Junutula
Guest Editor

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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly 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 2600 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

  • Antibody-drug conjugates
  • ADCs
  • Tumor antigen
  • Cytotoxic payload
  • Linker design
  • Therapeutic index
  • Site-specific conjugation
  • Cancer therapy
  • Targeted chemotherapy

Published Papers (4 papers)

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Research

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18 pages, 1490 KiB  
Article
Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE)
by Hsuan Ping Chang, Yuen Kiu Cheung and Dhaval K. Shah
J. Clin. Med. 2021, 10(6), 1332; https://doi.org/10.3390/jcm10061332 - 23 Mar 2021
Cited by 23 | Viewed by 5634
Abstract
Monomethyl auristatin E (MMAE) is one of the most commonly used payloads for developing antibody–drug conjugates (ADC). However, limited studies have comprehensively evaluated the whole-body disposition of MMAE. Consequently, here, we have investigated the whole-body pharmacokinetics (PK) of MMAE in tumor-bearing mice. We [...] Read more.
Monomethyl auristatin E (MMAE) is one of the most commonly used payloads for developing antibody–drug conjugates (ADC). However, limited studies have comprehensively evaluated the whole-body disposition of MMAE. Consequently, here, we have investigated the whole-body pharmacokinetics (PK) of MMAE in tumor-bearing mice. We show that while MMAE is rapidly eliminated from the plasma, it shows prolonged and extensive distribution in tissues, blood cells, and tumor. Highly perfused tissues (e.g., lung, kidney, heart, liver, and spleen) demonstrated tissue-to-plasma area under the concentration curve (AUC) ratios > 20, and poorly perfused tissues (e.g., fat, pancreas, skin, bone, and muscle) had ratios from 1.3 to 2.4. MMAE distribution was limited in the brain, and tumor had 8-fold higher exposure than plasma. A physiological-based pharmacokinetic (PBPK) model was developed to characterize the whole-body PK of MMAE, which accounted for perfusion/permeability-limited transfer of drug in the tissue, blood cell distribution of the drug, tissue/tumor retention of the drug, and plasma protein binding. The model was able to characterize the PK of MMAE in plasma, tissues, and tumor simultaneously, and model parameters were estimated with good precision. The MMAE PBPK model presented here can facilitate the development of a platform PBPK model for MMAE containing ADCs and help with their preclinical-to-clinical translation and clinical dose optimization. Full article
(This article belongs to the Special Issue Strategies and Challenges for the Next Generation of Antibody Drug Conjugates)
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20 pages, 3848 KiB  
Article
Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats
by Victor Yip, M. Violet Lee, Ola M. Saad, Shuguang Ma, S. Cyrus Khojasteh and Ben-Quan Shen
J. Clin. Med. 2021, 10(6), 1323; https://doi.org/10.3390/jcm10061323 - 23 Mar 2021
Cited by 12 | Viewed by 4428
Abstract
Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of [...] Read more.
Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY. Full article
(This article belongs to the Special Issue Strategies and Challenges for the Next Generation of Antibody Drug Conjugates)
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14 pages, 2713 KiB  
Article
Development of a Single-Step Antibody–Drug Conjugate Purification Process with Membrane Chromatography
by Juan Carlos Cordova, Sheng Sun, Jeffrey Bos, Srinath Thirumalairajan, Sanjeevani Ghone, Miyako Hirai, Ricarda A. Busse, Julia S. v. der Hardt, Ian Schwartz and Jieyu Zhou
J. Clin. Med. 2021, 10(3), 552; https://doi.org/10.3390/jcm10030552 - 2 Feb 2021
Cited by 6 | Viewed by 6559
Abstract
Membrane chromatography is routinely used to remove host cell proteins, viral particles, and aggregates during antibody downstream processing. The application of membrane chromatography to the field of antibody-drug conjugates (ADCs) has been applied in a limited capacity and in only specialized scenarios. Here, [...] Read more.
Membrane chromatography is routinely used to remove host cell proteins, viral particles, and aggregates during antibody downstream processing. The application of membrane chromatography to the field of antibody-drug conjugates (ADCs) has been applied in a limited capacity and in only specialized scenarios. Here, we utilized the characteristics of the membrane adsorbers, Sartobind® S and Phenyl, for aggregate and payload clearance while polishing the ADC in a single chromatographic run. The Sartobind® S membrane was used in the removal of excess payload, while the Sartobind® Phenyl was used to polish the ADC by clearance of unwanted drug-to-antibody ratio (DAR) species and aggregates. The Sartobind® S membrane reproducibly achieved log-fold clearance of free payload with a 10 membrane-volume wash. Application of the Sartobind® Phenyl decreased aggregates and higher DAR species while increasing DAR homogeneity. The Sartobind® S and Phenyl membranes were placed in tandem to simplify the process in a single chromatographic run. With the optimized binding, washing, and elution conditions, the tandem membrane approach was performed in a shorter timescale with minimum solvent consumption and high yield. The application of the tandem membrane chromatography system presents a novel and efficient purification scheme that can be realized during ADC manufacturing. Full article
(This article belongs to the Special Issue Strategies and Challenges for the Next Generation of Antibody Drug Conjugates)
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Review

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17 pages, 2834 KiB  
Review
Antibody-Oligonucleotide Conjugates: A Twist to Antibody-Drug Conjugates
by Julien Dugal-Tessier, Srinath Thirumalairajan and Nareshkumar Jain
J. Clin. Med. 2021, 10(4), 838; https://doi.org/10.3390/jcm10040838 - 18 Feb 2021
Cited by 48 | Viewed by 12410
Abstract
A summary of the key technological advancements in the preparation of antibody–oligonucleotide conjugates (AOCs) and the distinct advantages and disadvantages of AOCs as novel therapeutics are presented. The merits and demerits of the different approaches to conjugating oligonucleotides to antibodies, antibody fragments or [...] Read more.
A summary of the key technological advancements in the preparation of antibody–oligonucleotide conjugates (AOCs) and the distinct advantages and disadvantages of AOCs as novel therapeutics are presented. The merits and demerits of the different approaches to conjugating oligonucleotides to antibodies, antibody fragments or other proteins, mainly from the perspective of AOC purification and analytical characterizations, are assessed. The lessons learned from in vitro and in vivo studies, especially the findings related to silencing, trafficking, and cytotoxicity of the conjugates, are also summarized. Full article
(This article belongs to the Special Issue Strategies and Challenges for the Next Generation of Antibody Drug Conjugates)
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