Antibody Therapeutics最新文献

Antibody-drug conjugates (ADCs) have gained significant attention in biotherapeutics after several years of steady development. Among the multiple factors influencing ADC design, the conjugation method is one of the most critical parameters. This review classifies conjugation strategies into three categories: non-specific, site-specific but non-selective, and fully site-specific and selective methods. The characteristics; advantages and disadvantages; chemistry, manufacturing, and controls (CMC) potential; and clinical status of each conjugation strategy are discussed in detail. The site-specific and selective methods will yield more homogeneous ADC, which may influence the stability and pharmacokinetics (PK) profile of the ADC and then influence the final therapeutic outcome. Additionally, the review also explores challenges and future directions for developing novel conjugation strategies. This review presents the most prevalent conjugation techniques, providing a valuable resource for researchers in selecting conjugation technologies and advancing ADC development.

Background: AXL, a tyrosine kinase receptor, is over-expressed in many solid and hematologic cancers, promoting progression and poor clinical outcomes. It also contributes to resistance against chemotherapeutic agents, especially tyrosine kinase inhibitors, by upregulating AXL signaling or switching oncogenic pathways. These factors make AXL an attractive therapeutic target. However, early attempts with naked antibody therapies failed due to the high doses need for efficacy, and antibody-drug conjugates (ADCs) targeting AXL were hindered by off-tumor toxicities due to its expression on normal tissues.

Methods: To address these issues, we developed a novel, conditionally active biologic ADC, mecbotamab vedotin (BA3011), which selectively binds to AXL in the acidic tumor microenvironment. In healthy tissue, binding to AXL is substantially diminished due to a powerful selection mechanism utilizing naturally occurring, physiological chemicals referred to as Protein-associated Chemical Switches. BA3011 was tested in vitro and in vivo against AXL expressing cancer cells.

Results: Mecbotamab vedotin demonstrates the expected AXL, tumor-specific binding properties and effectively induced lysis of AXL-positive cancer cell lines in vitro. In vivo, mecbotamab vedotin exhibited potent and lasting antitumor effects in human cancer xenograft mouse models. Furthermore, in nonhuman primates, mecbotamab vedotin demonstrated excellent tolerability at doses of up to 5 mg/kg and maintained linker-payload stability in vivo.

Conclusions: These findings indicate that mecbotamab vedotin has the potential to be a robust and less toxic therapeutic agent, offering promise as a treatment for patients with AXL-positive cancers.

An antibody-drug conjugate (ADC), consisting of an antibody, a chemical linker, and a payload, can selectively deliver a highly cytotoxic payload to cancer cells and minimize the systemic toxicity of the payload by harnessing the selectivity of the antibody. However, many ADCs have unacceptable toxic effects due to the expression characteristics of target antigens, structural characteristics of antibodies, linker stability and payload properties, which have slowed their development progress. In this review, we describe the effects of the structure of each component of an ADC molecule on its toxicity, explore and discuss the toxicity profiles of various ADCs in the main body tissues/organs by using nonclinical and clinical data obtained from marketed ADCs, aiming to provide a reference for the development of novel ADC molecules and to facilitate related nonclinical and clinical studies.

Antibody-drug conjugates (ADCs) have emerged as a rapidly expanding class of therapeutics driven by their superior specificity and clinical efficacy. 14 out of 16 commercially approved ADCs are formulated as lyophilized forms because ADC is generally considered to be less stable than unmodified antibody. The formulation development for ADCs, particularly liquid formulation, presents unique challenges due to their intricate structural complexity, physicochemical properties, and degradation pathways. This review provides the first comprehensive analysis of formulation strategies employed in commercial ADCs. Furthermore, this review discusses the key areas of focus for ADCs throughout the formulation development workflow, spanning from the initial formulation development to the final stage of drug product manufacturing. In addition, we identify and analyze the distinctive technical challenges in ADC formulation development compared to unconjugated antibody, while proposing potential solutions to these challenges. Finally, we offer strategic perspectives on future directions in ADC formulation development to advance this promising therapeutic modality.

The overuse of antibiotics worldwide, especially during the Coronavirus pandemic, has raised concerns about the rise of antibiotic resistance and its side effects. Immunoglobulin Y, a natural protein that specifically targets foreign antigens, holds promise as a potential therapeutic option, particularly for individuals with sensitive immune systems. Despite numerous studies on IgY, the optimal administration method, effective dose, target antigen, and potential side effects of this antibody remain areas of active research and challenge. This review selected and evaluated articles published in the last ten years from databases such as PubMed and Science Direct with appropriate keywords discussing the therapeutic effects of immunoglobulin Y in human infections in vivo. Out of all the reviewed articles, 35 articles met the inclusion criteria. The results showed that the specific antibody against dental, respiratory, and skin infections has an acceptable effectiveness. In contrast, some infections, such as neurological infections, including tetanus and botulism, still need further investigation due to the short survival time of mice. On the other hand, reporting side effects such as antibody-dependent enhancement in some infections limits its use.

The effectiveness of therapeutic antibodies is often associated with their Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. These functions rely on interactions between Fc gamma receptors (FcγRs) on immune cells and the Fc region of antibodies. Genetic variations in these receptors, known as FcγR polymorphisms, can influence therapeutic outcomes by altering receptor expression levels, affinity, and function. This review examines the impact of FcγR polymorphisms on antibody therapy, emphasizing their role in developing and optimizing functional bioassays to assess product quality. Understanding these polymorphisms is essential for refining bioassays, which are crucial for accurately characterizing antibody products and ensuring consistency in manufacturing processes.

Photoimmunotherapy (PIT) involves the targeted delivery of a photosensitizer through antibody conjugation, which, upon binding to its cellular target and activation by external irradiation, induces localized toxicity. This approach addresses several limitations of conventional cancer therapies, such as chemo- and radiotherapies, which result in off-target effects that significantly reduce patient quality of life. Furthermore, PIT improves on the challenges encountered with photodynamic therapy (PDT), such as nonspecific localization of the photosensitizer, which often results in unintended toxicities. Although PIT was first proposed in the early 1980s, its clinical applications have been constrained by limitations in antibody engineering, conjugation chemistries, and optical technologies. However, recent advances in antibody-drug conjugate (ADC) research and the emergence of sophisticated laser technologies have greatly benefited the broader applicability of PIT. Notably, the first near-infrared photoimmunotherapy (NIR-PIT) treatment for head and neck cancer has been approved in Japan and is currently in phase III clinical trials in the USA. A significant advantage of PIT over traditional ADCs in cancer management is the agnostic nature of PDT, making it more adaptable to different tumor types. Specifically, PIT can act on cancer stem cells and cancer cells displaying treatment resistance and aggressive phenotypes-a capability beyond the scope of ADCs alone. This review provides an overview of the mechanism of action of NIR-PIT, highlighting its adaptability and application in cancer therapeutics, and concludes by exploring the potential of PIT in advancing cancer treatments.

Background: CD30 is a member of the tumor necrosis factor receptor superfamily. Recently, blocking CD30-dependent intracellular signaling has emerged as potential strategy for immunological regulation. Development of antibody-based CD30 antagonists is therefore of significant interest. However, a key challenge is that the bivalent form of natural antibody can crosslink CD30 molecules, leading to signal transduction even in the absence of specific ligand, CD153. Biparatopic antibodies (BpAbs) offer a solution, using two different variable fragments (Fvs) to bind distinct epitopes on a single antigen molecule. BpAbs format is an attractive alternative of natural antibody by potentially avoiding unwanted crosslinking and signaling induction.

Methods: We systematically characterized 36 BpAbs, each designed with pairs of Fvs binding to nine distinct epitopes across the CD30 extracellular domain. We first identified the precise epitope sites of the nine antibodies by assessing the binding to multiple orthologous CD30 proteins and mutants. We then produced the 36 BpAbs and analyzed their biological activities and binding modes.

Results: Among 36 BpAbs, we identified both potent ligand-independent agonists and ligand-blocking antagonists, with many displayed reduced signal activation, including 1:1-binding antagonists derived from AC10, a strong agonist developed for lymphoma therapy. Epitope dependency in reduced signaling activity was observed and associated with the flexible nature of CD30 protein.

Conclusions: We successfully developed antagonistic BpAbs against CD30 by controlling the stoichiometry of antibody-antigen binding mode. This study elucidated the mechanism of signaling induction, informing the design strategies of the development of biparatopic antibodies.

The development of targeted drugs for the treatment of systemic lupus erythematosus (SLE) is a promising area of research because targeted drugs are associated with a lower risk of severe side effects than systemic drugs. There are only two approved drugs based on monoclonal antibodies (a group of targeted drugs) for the treatment of SLE, so there is an unmet need for the development of new and improved antibody analogs. This review analyzes the effectiveness and safety of both already approved antibodies (anifrolumab and belimumab) for the treatment of SLE and antibodies under development with an assessment of their future prospects for entering the pharmaceutical market. In addition to the antibodies themselves, the choice of their therapeutic targets and what role the targets can play in the effectiveness and safety of the antibodies are analyzed here.

Background: Chimeric antigen receptor (CAR)-T-cell therapy is a breakthrough in the field of cancer immunotherapy, wherein T cells are genetically modified to recognize and attack cancer cells. Delivery of the CAR gene is a critical step in this therapy and is usually achieved by transducing patient T cells with a lentiviral vector (LV). Because the LV is an essential component of CAR-T manufacturing, there is a need for simple bioassays that reflect the mechanism of action (MOA) of the LV and can measure LV potency with accuracy and specificity. Common methods for LV quantification may overestimate functional titer and lack a functional readout of LV MOA.

Methods: We developed a bioluminescent reporter bioassay using Jurkat T cells stably expressing a luciferase reporter under the control of an nuclear factor of activated T cells (NFAT) response element and tested its suitability for measuring LV potency.

Results: Jurkat reporter cells can be transduced with CAR LV and combined with target cells, yielding a luminescent signal that is dependent on the identity and potency of the LV used. Bioluminescence was highly correlated with CAR expression. The assay is stability indicating and suitable for use in drug development and quality control settings.

Conclusions: We have developed a simple bioassay for potency testing of CAR LV. The bioassay represents a significant improvement over other approaches to LV quantification because it reflects the MOA of the LV and selectively detects fully functional viral particles, making it ideal for inclusion in a matrix of in-process quality control assays for CAR LV.