Antibody-Drug Conjugate

In this review we summarize the current evidence describing the management of patients with relapsed/refractory MCL and outline the various novel therapeutics that have been developed over the past two decades. We also describe how overall response rates, complete response rates, duration of responses, and life expectancy have dramatically increased with the introduction of novel therapies, particularly covalent Bruton Tyrosine Kinase inhibitors (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy. The most recent emerging options for patients with progressive disease following BTKi or CAR-T, including non-covalent BTKi, antibody-drug conjugates, Bcl-2 inhibitors, and bispecific antibodies, may further improve response rates and outcomes...

Nanoparticle (NP) functionalization with specific ligands enhances targeted cancer therapy and imaging by promoting receptor recognition and improving cellular uptake. This review focuses on recent research exploring the interaction between cancer cell-expressed chemokine receptor 4 (CXCR4) and ligand-conjugated NPs, utilizing small molecules, peptides, and antibodies. Active NP targeting has shown improved tumor targeting and reduced toxicity, enabling precision therapy and diagnosis.However, challenges persist in the clinical translation of targeted NPs due to issues with biological response, tumor accumulation, and maintaining NP quality at an industrial scale...

Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR-DLBCL have not been replicated in routine care cohorts, as RR-DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR-DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study...

Nonionic surfactant excipients (NISEs) are commonly added to biologics formulations to mitigate the effects of stress incurred by the active biotherapeutic during manufacturing, transport, and storage. During manufacturing, NISEs are added by dilution of a stock solution directly into a protein formulation, and their accurate addition is critical in maintaining the quality and integrity of the drug product and thus ensuring patient safety. This is especially true for the common NISEs, polysorbates 20 and 80 (PS20 and PS80, respectively) and poloxamer 188 (P188)...

BACKGROUND: HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody-drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models...

No abstract text is available yet for this article.

Initial studies indicated that NECTIN4 expression is widespread in metastatic urothelial cancer (mUC), which led to approval of the anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) for unselected patients with mUC. However, the recent literature suggests that there has been overestimation of membranous NECTIN4 expression in UC, which is a prerequisite for EV binding. It is well established from the development of Her2-targeting ADCs that treatment response is strongly dependent on membranous expression level of the relevant target antigen...

Platinum-based chemotherapy plus PD-1 axis blockade is the standard of care in the front-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Despite the robust and consistent increase of long-term survival with PD-1 axis inhibition, the magnitude of the benefit from immunotherapy appears lower as compared to other solid tumors. Several immune evasive mechanisms have been shown to be prominently altered in human SCLC, including, among others, T cell exclusion, downregulation of components of the MHC-class I antigen processing and presentation machinery, or upregulation of macrophage inhibitory checkpoints...

Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC...

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals...

No abstract text is available yet for this article.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed...

In the era of precision medicine, Antibody-Drug Conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well-established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases...

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) consisting of a humanised, anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody covalently linked to a topoisomerase I inhibitor cytotoxic payload (DXd). The high drug-to-antibody ratio (8:1) ensures a high DXd concentration is delivered to target tumour cells, following internalisation of T-DXd and subsequent cleavage of its tetrapeptide-based linker. DXd's membrane-permeable nature enables it to cross cell membranes and potentially exert antitumour activity on surrounding tumour cells regardless of HER2 expression...

Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies...

Antibody-drug conjugates (ADCs) are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells, thereby attracting considerable attention in precise oncology therapy. Cetuximab (Cet) is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma (cSCC); however, its anti-tumor activity is limited to a single use...

Endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the first-line standard treatment for most patients with hormone receptor-positive (HR+) and human epidermal growth receptor 2-negative (HER2-) metastatic or advanced breast cancer. However, the majority of tumors response to and eventually develop resistance to CDK4/6is. The mechanisms of resistance are poorly understood, and the optimal postprogression treatment regimens and their sequences continue to evolve in the rapidly changing treatment landscape...

In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities, of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Among the 12 therapeutic antibodies approved by the US FDA, 8 were relatively standard IgG formats, 3 were bivalent, bispecific antibodies and 1 was a trivalent, bispecific antibody...

INTRODUCTION: The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing, particularly among younger populations. It is projected that the number of new cases will increase by almost 50% by 2040, with market revenues expected to triple in the same period. Despite the recent introduction of immune checkpoint inhibitors (ICIs) into the therapeutic armamentarium, the vast majority of patients with recurrent and/or metastatic (R/M) HNSCC fail to derive durable benefits from systemic therapy...

Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug resistance in advanced breast cancer limits the therapeutic output of treatment. The leading cause of resistance in breast cancer is endocrine and hormonal imbalance, particularly in triple negative and HER2 positive breast cancers. The efflux of drugs due to p-gp's activity is another leading cause of resistance. Breast cancer resistant protein also contributes significantly...