The emergence of b-cell maturation antigen (BCMA) targeting immunotherapy in multiple myeloma

Objective Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium over the last decade, multiple myeloma remains an incurable malignancy. B-cell maturation antigen (BCMA) is an antigen expressed on the surface on plasma cells that can be targeted by novel mechanisms of action including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapy. This review summarizes the clinical application and development of approved and investigational immunotherapies targeting BCMA. Data Sources A search of the PubMed database was conducted using the following search terms: BCMA, CAR T, myeloma, belantamab mafodotin, and bispecific. Ongoing clinical trials, as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents targeting BCMA were evaluated. Prescribing information was also reviewed. Data Summary Since the discovery of BCMA as a target for myeloma, researchers have developed antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies as novel treatment modalities for myeloma patients. Belantamab mafodotin and idecabtagene vicleucel represent currently available therapies and ongoing trials have demonstrated the efficacy and safety of bispecifics and other BCMA targeting therapies. Conclusion BCMA targeting antibody drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies have demonstrated clinical activity in myeloma patients and represent novel therapies in multiple myeloma treatment paradigm.

Divinylpyrimidine reagents generate antibody-drug conjugates with excellent in vivo efficacy and tolerability

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first...

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

Glioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.

Current state of clinical development of TROP2-directed antibody–drug conjugates for triple-negative breast cancer

SummaryAntibody–drug conjugates (ADCs) against numerous molecular targets are currently being developed for the treatment of breast cancer (BCa). While the first ADC directed against Her2, namely trastuzumab–emtansine, was approved several years ago, targeting of TROP‑2, an epithelial cell marker overexpressed in approximately 80% of triple-negative breast cancers (TNBC) has gained interest through positive clinical data reported for the compound sacituzumab–govitecan (SG) resulting from the phase 3 ASCENT trial. This short review summarizes the data that led to approval of SG and to take a closer look at the state of clinical development of other ADCs targeting TROP‑2 in TNBC.

Antibody-Drug-Conjugates for Breast Cancer

Background Despite the advances that have been made to improve conventional chemotherapies, their use is limited by a narrow therapeutic window based on off-target toxicities. Antibody-drug-conjugates (ADCs) are composed of an antibody and a toxic payload covalently coupled by a chemical linker. They constitute an elegant means to tackle the limitations of conventional chemotherapeutics by selectively delivering a highly toxic payload directly to target cells and thereby increasing efficacy of the delivered cytotoxic but at the same time limiting systemic exposure and toxicities. As such they appear inspired by Paul Ehrlich´s concept of a “magic bullet”, which he envisioned as drugs that go directly to their target to attack pathogens but remain harmless in healthy tissues. Summary The concept of conjugating drugs to antibodies via chemical linkers is not new. As early as in the 1960s researchers started to investigate such ADCs in animal models and first clinical trials based on mouse antibodies began in the 1980s. Although the concept appears relatively straightforward, ADCs are highly complex molecules, and it took several decades of research and development until the first ADC became approved by the FDA in 2000 and the second followed not until 11 years later. The development of an effective ADC is highly demanding, and each individual component of an ADC must be optimized: the target, the antibody, the linker and its conjugation chemistry as well as the cytotoxic payload. Today there are 9 approved ADCs overall and 3 for breast cancer. So, the pace of development seems to pick up with over 100 candidates in various stages of clinical development. Many ADCs of the newest generation are optimized to elicit a so-called bystander effect, to increase efficacy and tackle heterogneous antigen expression. This approach requires a balancing of efficacy and systemic toxicity. Hence, ADCs based on their complex biology cause relevant toxicities, which are characteristic for each specific compound and may include hematologic toxicities, elevated transaminases, gastrointestinal events, pneumonitis but also ocular toxicities as well as others many physicians may initially not be very familiar with. Management of the side effects will be key to the successful clinical use of these potent drugs. Key Messages This review focusses on the clinical experience with ADCs approved in breast cancer as well as promising candidates in late-stage clinical development. We will discuss the mode of action, biology, and composition of ADCs and how each of these crucial components influences their properties and efficacy.