**4. BCMA-targeting antibody-drug complexes**

The cytokines BAFF (B-cell activating factor) and APRIL (a proliferationinducing ligand) have received much attention in recent years for their roles in the pathophysiology of autoimmune diseases [40]. In addition, there is evidence that these two homologous members of the tumor necrosis factor (TNF) superfamily play roles in myeloma cell viability and proliferation [41]. Two other TNF family members - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), located on the surface of myeloma cells, serve as ligands for both BAFF and APRIL [42]. While the respective BAFF and APRIL inhibitors, atacicept and tabalumab (LY2127399), as well as the anti-APRIL mAb BION-1301, showed poor efficacy in MM trials [43–45], BCMA has surfaced as a compelling target in anti-myeloma drug research [46].

BCMA normally plays a key role in B-cell differentiation into plasma cells [47]. Myeloma cells, whether from cell lines or patient samples, exhibit not only consistent and virtually exclusive elevation of BCMA levels and its mRNA during malignant transformation but also at similar levels during the various stages of MM from previously untreated to relapse [48]. A soluble form of BCMA (sBCMA), which results from the shedding of BCMA from the plasma cell surface by the action of γ-secretase, is an important factor that, by lowering the density of the target antigen while also providing a soluble decoy, potentially limits the efficacy of BCMA blockers in clinical development, accounting for the inclusion of γ-secretase inhibitors in a number of BCMA-targeted trials [49].

Removal of several of the fucosyl groups normally found in the N-linked biantennary complex oligosaccharides in the Fc region of IgG antibodies is a wellestablished approach for enhancing ADCC through binding of FcγIIIa receptors on NK cells [50]. One such anti-BCMA mAb is the afucosylated antibody-drug conjugate (ADC) belantamab mafodotin (Blenrep®, GSK2857916), in which the antibody is coupled to the microtubule inhibitor monomethylauristatin F (MMAF) through a protease-resistant maleimidocaproyl linker. While the antibody component disrupts BAFF/APRIL myeloma cell signaling by binding to the BCMA receptor to induce ADCC, the MMAF component causes cell cycle arrest at the G2/M interface [51]. Belantamab mafodotin continues to be the subject of the DREAMM series of trials in RRMM patients. An early exploratory study (NCT02064387, DREAMM-1) found an ORR of 60% in 35 heavily pre-treated RRMM patients when the immunoconjugate was used as a single agent [52]. This encouraging response level dropped to 31% (30/97) in RRMM patients refractory to proteasome inhibitors, immunomodulators, and/or anti-CD38 therapy, who received the drug as monotherapy at 2.5 mg./Kg. in the ensuing phase II DREAMM-2 trial (NCT03525678) [53]. However, the efficacy level was considered comparable to that observed with other therapies for RRMM patients with similar

**143**

α-amanitin [62].

**5. T-cell-engaging bispecific antibodies**

*Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma*

numbers of prior therapies. Analysis of adverse event data in the DREAMM-2 trial concluded that belantamab mafodotin exhibits an acceptable safety profile with ocular toxicity, primarily in the form of keratopathy as the most commonly reported adverse event and attributable to the microtubule-inhibitor payload [54], presenting the greatest concern. Based on these data, in August, 2020, belantamab mafodotin was approved by the FDA, under the provisions of accelerated review, as monotherapy for RRMM patients who have received at least four prior treatments that included an immunomodulator, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [55]. In addition to these two milestone studies, a phase II trial (NCT04126200; DREAMM-5) has been initiated that includes belantamab mafodotin monotherapy with two T-cell costimulatory agonist mAbs – the OX40-targeting GSK3174998 and the inducible co-stimulator (ICOS) GSK3359609, along with nirogacestat (PF-03084014), a γ-secretase inhibitor [56]. The ADC plus low-dose dexamethasone also is incorporated into four phase III investigations that include standard therapies such as: pomalidomide (NCT04162210; DREAMM-3, RRMM); bortezomib and daratumumab (NCT04246047; DREAMM-7, RRMM); pomalidomide and bortezomib (NCT04484623; DREAMM-8, RRMM); and lenalidomide and bortezomib (NCT04091126; DREAMM-9, NDMM) [57]. Another BCMA-targeted ADC that has elicited much interest for its antimyeloma action is MEDI2228, which is comprised of a fully human mAb attached

to a minor-groove binding pyrrolobenzodiazepine (tesirine) payload via a protease-cleavable valine-alanine linker [58]. Release of the warhead following internalization of the immunoconjugate and trafficking to the lysosome results in DNA damage and subsequent apoptosis. Preclinical studies in mice revealed this agent's potent anti-myeloma activity even when clinically significant levels of sBCMA were present [59]. Currently, MEDI2228 is the subject of a phase I clinical trial (NCT03489525) to determine appropriate dosing as monotherapy in RRMM patients; however, no results have been reported as yet. Another anti-BCMA ADC that has entered clinical studies for MM is AMG 224 (NCT02561962), comprised of a maytansine analog connected to a non-cleavable 4-(*N*-maleimidomethyl) cyclohexane-1-carboxylate linker [60]. CC-99712 is yet another BCMA-targeted ADC (undisclosed composition) that recently entered a clinical trial (NCT04036461) for RRMM. Other anti-BCMA ADC mAbs that have demonstrated promise in preclinical work but for which human studies have not yet begun include two proprietary products, referred to as BCMA-077 and BCMA-024 [61], and HDP-101, in which the conjugate is the potent RNA polymerase II subunit A (POLR2A) inhibitor

The T-cell-engaging bispecific antibody (T-BsAb) concept, originally developed by Nisonoff in 1961 [63], is based on the design of a dual-targeting antibody whereby one arm initially binds to the T-cell CD3 co-receptor complex while the other arm is subsequently directed to a tumor-associated antigen. The immunological synapse created between the two cells causes release of two cytolytic-initiating proteins: perforin, which causes formation of transmembrane pores in the malignant cell and granzyme B, which traverses the pores thus produced to initiate tumor cell apoptosis. The T-BsAb strategy differs from normal T-cell mediated cytotoxicity by removing requirements for costimulatory signals, formation of an antigen-major histocompatibility complex (MHC), and for *ex vivo* T-cell manipulation, thus permitting the possibility of "off-the-shelf" product manufacture. Furthermore, persistent T-cell activation enables polyclonal expansion of T memory cells. In addition, the

*DOI: http://dx.doi.org/10.5772/intechopen.94196*

#### *Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma DOI: http://dx.doi.org/10.5772/intechopen.94196*

*Monoclonal Antibodies*

included with elotuzumab [39].

**4. BCMA-targeting antibody-drug complexes**

inhibitors in a number of BCMA-targeted trials [49].

with or without lenalidomide. The cohort receiving elotuzumab exhibited a PFS of 19.4 months and an ORR of 68% at one year and 41% at two years, compared to 14.9 months and 57% and 27% for the control [35]. These results were confirmed further by a subsequent four-year follow-up study [36]. Similar benefits of elotuzumab in RRMM were observed in combination with pomalidomidedexamethasone in the ELOQUENT-3 trial (NCT02654132) [37], which included patients refractory to both lenalidomide and a proteasome inhibitor and resulted in the 2018 FDA approval of this combination [38]. Favorable data also have been generated in a trial (NCT01478048) in which bortezomib-dexamethasone was

The cytokines BAFF (B-cell activating factor) and APRIL (a proliferationinducing ligand) have received much attention in recent years for their roles in the pathophysiology of autoimmune diseases [40]. In addition, there is evidence that these two homologous members of the tumor necrosis factor (TNF) superfamily play roles in myeloma cell viability and proliferation [41]. Two other TNF family members - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), located on the surface of myeloma cells, serve as ligands for both BAFF and APRIL [42]. While the respective BAFF and APRIL inhibitors, atacicept and tabalumab (LY2127399), as well as the anti-APRIL mAb BION-1301, showed poor efficacy in MM trials [43–45], BCMA

has surfaced as a compelling target in anti-myeloma drug research [46].

BCMA normally plays a key role in B-cell differentiation into plasma cells [47]. Myeloma cells, whether from cell lines or patient samples, exhibit not only consistent and virtually exclusive elevation of BCMA levels and its mRNA during malignant transformation but also at similar levels during the various stages of MM from previously untreated to relapse [48]. A soluble form of BCMA (sBCMA), which results from the shedding of BCMA from the plasma cell surface by the action of γ-secretase, is an important factor that, by lowering the density of the target antigen while also providing a soluble decoy, potentially limits the efficacy of BCMA blockers in clinical development, accounting for the inclusion of γ-secretase

Removal of several of the fucosyl groups normally found in the N-linked biantennary complex oligosaccharides in the Fc region of IgG antibodies is a wellestablished approach for enhancing ADCC through binding of FcγIIIa receptors on NK cells [50]. One such anti-BCMA mAb is the afucosylated antibody-drug conjugate (ADC) belantamab mafodotin (Blenrep®, GSK2857916), in which the antibody is coupled to the microtubule inhibitor monomethylauristatin F (MMAF) through a protease-resistant maleimidocaproyl linker. While the antibody component disrupts BAFF/APRIL myeloma cell signaling by binding to the BCMA receptor to induce ADCC, the MMAF component causes cell cycle arrest at the G2/M interface [51]. Belantamab mafodotin continues to be the subject of the DREAMM series of trials in RRMM patients. An early exploratory study (NCT02064387, DREAMM-1) found an ORR of 60% in 35 heavily pre-treated RRMM patients when the immunoconjugate was used as a single agent [52]. This encouraging response level dropped to 31% (30/97) in RRMM patients refractory to proteasome inhibitors, immunomodulators, and/or anti-CD38 therapy, who received the drug as monotherapy at 2.5 mg./Kg. in the ensuing phase II DREAMM-2 trial (NCT03525678) [53]. However, the efficacy level was considered comparable to that observed with other therapies for RRMM patients with similar

**142**

numbers of prior therapies. Analysis of adverse event data in the DREAMM-2 trial concluded that belantamab mafodotin exhibits an acceptable safety profile with ocular toxicity, primarily in the form of keratopathy as the most commonly reported adverse event and attributable to the microtubule-inhibitor payload [54], presenting the greatest concern. Based on these data, in August, 2020, belantamab mafodotin was approved by the FDA, under the provisions of accelerated review, as monotherapy for RRMM patients who have received at least four prior treatments that included an immunomodulator, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [55]. In addition to these two milestone studies, a phase II trial (NCT04126200; DREAMM-5) has been initiated that includes belantamab mafodotin monotherapy with two T-cell costimulatory agonist mAbs – the OX40-targeting GSK3174998 and the inducible co-stimulator (ICOS) GSK3359609, along with nirogacestat (PF-03084014), a γ-secretase inhibitor [56]. The ADC plus low-dose dexamethasone also is incorporated into four phase III investigations that include standard therapies such as: pomalidomide (NCT04162210; DREAMM-3, RRMM); bortezomib and daratumumab (NCT04246047; DREAMM-7, RRMM); pomalidomide and bortezomib (NCT04484623; DREAMM-8, RRMM); and lenalidomide and bortezomib (NCT04091126; DREAMM-9, NDMM) [57].

Another BCMA-targeted ADC that has elicited much interest for its antimyeloma action is MEDI2228, which is comprised of a fully human mAb attached to a minor-groove binding pyrrolobenzodiazepine (tesirine) payload via a protease-cleavable valine-alanine linker [58]. Release of the warhead following internalization of the immunoconjugate and trafficking to the lysosome results in DNA damage and subsequent apoptosis. Preclinical studies in mice revealed this agent's potent anti-myeloma activity even when clinically significant levels of sBCMA were present [59]. Currently, MEDI2228 is the subject of a phase I clinical trial (NCT03489525) to determine appropriate dosing as monotherapy in RRMM patients; however, no results have been reported as yet. Another anti-BCMA ADC that has entered clinical studies for MM is AMG 224 (NCT02561962), comprised of a maytansine analog connected to a non-cleavable 4-(*N*-maleimidomethyl) cyclohexane-1-carboxylate linker [60]. CC-99712 is yet another BCMA-targeted ADC (undisclosed composition) that recently entered a clinical trial (NCT04036461) for RRMM. Other anti-BCMA ADC mAbs that have demonstrated promise in preclinical work but for which human studies have not yet begun include two proprietary products, referred to as BCMA-077 and BCMA-024 [61], and HDP-101, in which the conjugate is the potent RNA polymerase II subunit A (POLR2A) inhibitor α-amanitin [62].
