The Fc region of antibodies is vital for most of their physiological functions, many of which are engaged through binding to a range of Fc receptors. However, these same interactions are not always h...

By combining and cross-checking data from the World Health Organization’s lists of international nonproprietary names with three other databases, we assembled a dataset of amino acid sequences of 8...

Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Man...

The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathep...

The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well-established and clinically proven drug delivery approach to improve the pharmacokinetics and p....

Degradation of therapeutic monoclonal antibodies (mAbs) is a major concern as it affects efficacy, shelf-life, and safety of the product. Taurine, a naturally occurring amino acid, is investigated in ...

Bioconjugation of polymers to proteins is a method to impart improved stability and pharmacokinetic properties to biologic systems. However, the precise effects of polymer architecture on the resultin...

Antibody–drug conjugates (ADCs) are increasingly prevalent as investigational and marketed treatments for a variety of cancers and other diseases. The structures of most ADCs comprise a small-molecule component (the drug-linker) chemically conjugated to a monoclonal antibody, and this hybrid construct presents a number of challenges for Chemistry, Manufacturing, and Controls (CMC) development. A Small Molecule Considerations for ADC Development Working Group (WG) has been established within the IQ Consortium to serve as a forum for biopharmaceutical industry companies to discuss development strategies for ADCs, with a focus on the drug-linker portion. The preceding paper from the WG presented results from a benchmarking survey of IQ member companies on a number of topics relating to drug-linker development. One of the key findings was that ultrafiltration/diafiltration (UF/DF) is used by all responding companies for purification of the ADC following the conjugation step and is a critical operation for control of small-molecule impurities in the ADC drug substance. UF/DF is well established in monoclonal antibody processing, but to date, there are relatively few literature reports detailing its application to ADCs. To help address this gap, this manuscript presents results and analysis from a more focused survey of IQ member companies on the application of UF/DF for post-conjugation purification of ADCs. Insight is provided into practical considerations such as common operating parameters, relative efficiency of removal of different types of impurities, technical challenges, and application of emerging technologies. In addition, recommendations are offered on where to start when developing a UF/DF process for a new ADC. The overall goals are to provide an overview of current industry practices for UF/DF purification of ADCs and to spur further communication and innovation in this area.

Abstract. In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-b...

Proteolysis targeting chimera (PROTACs) provide a novel therapeutic approach that is revolutionizing drug discovery. The success of PROTACs largely de…

Abstract. Monomethyl auristatin E (MMAE) is a potent tubulin inhibitor that is used as the payload for four FDA-approved antibody–drug conjugates (ADC). Deconjugated MMAE readily diffuses into untarge...

Typical antibody–drug conjugates (ADCs) with valine–alanine linkage, often conjugated with the amino group in payloads, face challenges when interacting with hydroxyl group-containing payloads. Herein, we introduced a transformative Val–Ala-based double self-immolative linker-payload platform, reshaping ADCs by optimizing hydroxyl group-containing payload integration. Utilizing this platform, FDA022-BB05 was successfully conjugated with the hydroxyl group-containing payload DXd using trastuzumab (FDA022) as the monoclonal antibody (mAb). FDA022-BB05 demonstrated enhanced stability, effective cathepsin B sensitivity, reduced cell proliferation, increased bystander killing, and targeted delivery. Notably, acute toxicity evaluations in diverse preclinical models indicated favorable safety profiles and tolerability, with a broad therapeutic index in HER2-positive and -negative xenografts. Overall, these compelling findings support the promising therapeutic potential of FDA022-BB05, emphasizing the significance of diverse linker-payload platform strategies. This ADC is a valuable addition to targeted cancer therapy development, currently advancing through phase I clinical trials.

Ferritin molecules, hollow protein spheres that store and release iron as needed, also hold promise for disease diagnosis, drug delivery, and vaccine development. Almost all organisms produce ferritin...

Macrocycles are one of nature’s preferred choices to generate large but cell-permeable bioactive molecules. Macrocyclization is increasingly prominent in medicinal chemistry beyond natural products, especially for difficult-to-drug targets. However, strategies to best exploit the potential of macrocycles are only beginning to emerge. Here we survey drug discovery campaigns from the past decade that cumulated in advanced macrocyclic drug-like compounds or drug candidates. Most macrocycles were conceived by ring closing based on U- or C-shaped bioactive conformations observed in co-crystal structures. We focus on the key step from linear precursors to the first macrocycle and the follow-up optimization of the resulting macrocyclic scaffold. Conformational control recurrently emerged as a key factor for macrocycle properties and linkers as an opportunity for optimization. With increasingly challenging drug targets, we expect these trends to become more prominent and relevant.

A biological boronate: An orthogonal tRNA/aminoacyl-tRNA synthetase pair has been evolved for the genetic incorporation of a boronic acid into proteins. This amino acid has been used to purify protei...

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its cl...

Methodologies for the self-immolative release of amide motifs remain scarce despite the prevalence of amides in molecules. Herein, is presented a general and comprehensive strategy for the selective ...