Antibody-drug conjugates (ADCs) are a rapidly expanding class of biotherapeutics that utilize antibodies to selectively deliver cytotoxic drugs to the tumor site. As of May 2021, the U.S. Food and Drug Administration (FDA) has approved ten ADCs, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, and Zynlonta™ as monotherapy or combinational therapy for breast cancer, urothelial cancer, myeloma, acute leukemia, and lymphoma. In addition, over 80 investigational ADCs are currently being evaluated in approximately 150 active clinical trials. Despite the growing interest in ADCs, challenges remain to expand their therapeutic index (with greater efficacy and less toxicity). Recent advances in the manufacturing technology for the antibody, payload, and linker combined with new bioconjugation platforms and state-of-the-art analytical techniques are helping to shape the future development of ADCs. This review highlights the current status of marketed ADCs and those under clinical investigation with a focus on translational strategies to improve product quality, safety, and efficacy.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health. At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide. Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S. National Library of Medicine (clinicaltrials.gov), results that can clarify benefits and risks of candidate therapies are only gradually becoming available. We herein describe recent advances in understanding SARS-COV-2 pathobiology and potential therapeutic targets that are involved in viral entry into host cells, viral spread in the body, and the subsequent COVID-19 progression. We highlight two major lines of therapeutic strategies for COVID-19 treatment: 1) repurposing the existing drugs for use in COVID-19 patients, such as antiviral medications (e.g., remdesivir) and immunomodulators (e.g., dexamethasone) which were previously approved for other disease conditions, and 2) novel biological products that are designed to target specific molecules that are involved in SARS-COV-2 viral entry, including neutralizing antibodies against the spike protein of SARS-COV-2, such as REGN-COV2 (an antibody cocktail) and LY-COV555, as well as recombinant human soluble ACE2 protein to counteract SARS-COV-2 binding to the transmembrane ACE2 receptor in target cells. Finally, we discuss potential drug resistance mechanisms and provide thoughts regarding clinical trial design to address the diversity in COVID-19 clinical manifestation. Of note, preventive vaccines, cell and gene therapies are not within the scope of the current review.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin–angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.

Background Neutralizing antibodies against SARS-CoV-2 are a vital component in the fight against COVID-19 pandemic, having the potential of both therapeutic and prophylactic applications. Bispecific antibodies (BsAbs) against SARS-CoV-2 are particularly promising given their ability to bind simultaneously to two distinct sites of the receptor binding domain (RBD) of the viral spike protein. Such antibodies are complex molecules associated with multi-faceted mechanisms of action (MoA) which require appropriate bioassays to ensure product quality and manufacturing consistency. Methods We developed procedures for biolayer interferometry (BLI) and a cell-based virus neutralization assay, the focus reduction neutralization test (FRNT). Using both assays, we tested a panel of five bispecific antibodies (BsAbs) against different spike variants (Ancestral, Delta, and Omicron) to evaluate the use of these analytical methods in assessing binding and neutralization activities of anti-SARS-CoV-2 therapeutics. Results We found comparable trends between BLI-derived binding affinity and FRNT-based virus neutralization activity. Antibodies that displayed high binding affinity against a variant were often followed by potent neutralization at lower concentrations whereas those with low binding affinity also demonstrated reduced neutralization activity. Conclusion The results support the utility of BLI and FRNT assays in measuring variant-specific binding and virus neutralization activity of anti-SARS-CoV-2 antibodies. Statement of significance Bispecific antibodies are a promising class of therapeutics against SARS-CoV-2. BLI coupled with FRNT assays can be used to characterize the binding and neutralization activity of these antibodies against specific SARS-CoV-2 variants.

Chemotherapy is inherently associated with side effects due to its poor selectivity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology promises to overcome barriers of classical chemotherapy by utilizing monoclonal antibodies to deliver potent payloads to selected target cancer cells. The antibody and cytotoxic payload are joined by a chemical linker resulting in an agent with the prospect of increased selectivity, anti-cancer activity, and improved systemic circulation. As of 2019, the US Food and Drug Administration (FDA) has approved five ADCs with cancer indications, including brentuximab vedotin for treatment of CD30-expressing lymphomas, trastuzumab emtansine for Her2-positive breast cancer, inotuzumab ozogamicin for CD22-positive acute lymphoblastic leukemia (ALL), gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia (AML), and polatuzumab vedotin for diffuse large B-cell lymphoma (DLBCL). Currently, there are about 80 ADCs under clinical development in nearly 130 clinical trials. Despite initial success, there are still many challenges in the development of ADCs with respect to their safety and efficacy profiles. In this study, we aim to survey the recent efforts in the design and development of ADCs. We have focused on site-specific conjugation methods for producing homogenous ADCs with consistent drug-antibody ratio (DAR) - a challenge often observed in conventional conjugation methods. This information is further discussed with respect to the ADC interaction with target cells to elicit cytotoxicity. The survey results will be presented, giving perspective on technical considerations for ADC design towards better correlation between preclinical and clinical results and overall safer and more efficacious products. Citation Format: Alexis Dean, Julianne Twomey, Baolin Zhang. Targeting cancer with antibody-drug conjugates: Promises and challenges [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2861.