Antibody-drug conjugate therapies in multiple myeloma—what’s next on the horizon?

Targeted immunotherapy has arisen over the past decade to the forefront of cancer care. Notably, targeted therapies such as antibody-drug conjugates (ADCs) are becoming more recognized for a novel approach in cancer treatment. The mechanism of action of ADCs incorporates a monoclonal antibody portion directed against the tumor cell antigen and attached to the tumoricidal portion via chemical linkage. The binding of the monoclonal antibody portion allows for tumor cell internalization of the ADC and precise release of the toxic payload within the cancer cell. Multiple myeloma (MM) is an incurable cancer for which belantamab mafodotin was the first-in-class ADC to achieve United States Food and Drug Administration (FDA) approval for treatment of this disease. Clinical trials are currently evaluating other ADCs in the treatment of MM. In this review, a look at the current ADCs being tested in MM clinical trials with a focus on those that are more promising and a potential next-in-line for FDA approval for treatment of MM is discussed.

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.

CD45-targeted antibody-drug-conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with non-malignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current genotoxic conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting use of this potentially curative treatment beyond malignant disorders. Minimizing genotoxic conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. Here we report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multi-lineage donor cell engraftment. Conditioning with CD45-ADC (3mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pre-transplant CD45-ADC (3mg/kg) combined with low-dose TBI (150cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pre-transplant TBI (50cGy) and post-transplant Rapamycin, Cytoxan or a JAK inhibitor, 90-100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5mg/kg), CD45-ADC as a single agent was sufficient for rapid, high level multi-lineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced intensity conditioning.

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...