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

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

therapeutically relevant properties of constructs may be fine-tuned to optimization by altering biodistribution characteristics and the relative binding affinities of each arm for their respective targets [64].

Amgen's proprietary BiTE® platform represents an innovative subclass of T-BsAb in which tandem single-chain variable fragments (scFvs) provide the crosslink [65]. The first successful application of BiTE® technology was the CD3-CD19 cross-linking construct blinatumomab (Blincyto®), which was approved by the FDA in 2014 for Philadelphia chromosome-negative B-cell precursor acute lymphocytic leukemia (B-cell ALL). Although a single trial (NCT03173430) of blinatumomab in RRMM patients had to be terminated because of "slow patient accrual", the majority of myeloma-related work using BiTE® constructs have been based on recombinant antibodies designed to cross-link surface tumor-specific T-cell CD3ζ chains and targeted myeloma cell BCMA.

Initial results with the BCMAxCD3 BiTE® product AMG 420 (BI-836909), which was accorded fast-track status by the FDA in 2018, showed an ORR of 31% in 42 RRMM patients, including seven of ten patients refractory to at least two lines of therapy who received the maximum tolerated dose of 400 μg/day. Infections and polyneuropathy were the most serious adverse events noted in this trial. Cytokine release syndrome (CRS; cytokine storm), predominantly grade 1, was observed in 38% of patients in the study [66, 67]. Monotherapy with AMG 701, a related BiTE® construct with a longer serum half-life than AMG 420, currently is the focus of a phase I trial (NCT03287908) for RRMM. Data generated in a preclinical investigation suggests that future consideration of a trial of AMG 701 in combination with an immunomodulator may be warranted [68]. In addition, two other BCMAxCD3 bispecific antibodies from Regeneron, REGN5458 (NCT03761108) and REGN5459 (NCT04083534), are in phase I RRMM studies. Preliminary data on the first three patients treated with the former agent have been reported [69].

Following favorable safety results in a monkey model [70], two phase I RRMM clinical trials of the BCMAxCD3 bispecific teclistamab (JNJ-64007957) have been initiated. In addition to a dose-escalation study (NCT03145181), this agent has been incorporated into a trial (NCT04108195) that includes subcutaneous daratumumab and talquetamab (JNJ-64407564), a CD3xGPRC5D bispecific construct. Another BCMAxCD3 formatted product under scrutiny for RRMM is PF-06863135 (PF-3135) (NCT03269136), the result of hinge-mutation engineering of an IgG2a backbone [71]. CC-93269, a T-cell engager whose arms bind in a 2 + 1 arrangement, monovalently to CD3ε and bivalently to BCMA, is another member of this class in a myeloma-based trial (NCT03486067) [72].

TNB-383B, a BCMAxCD3 T-BsAb resulting from collaboration between Tenebio and Abbvie and designated as an orphan drug by the FDA, differs from other drugs in this class in that its structure consists of a single immunoglobulin light chain and two variable heavy chains. The product, which recently began a phase I trial for RRMM (NCT03933735), is noteworthy for its strong T-cell activation kinetics and low affinity anti-CD3 arm, which results in reduced release of cytokines while retaining high cytotoxicity toward myeloma cells [73]. A number of other bispecific antibodies have exhibited promise for RRMM in preclinical work. These include TNB-381 M [74], FPA-151 [74], EM801 [48], and AP163 [75]. HPN217, developed by Harpoon Therapeutics, is a tri-specific antibody possessing three binding domains in a single chain – a C-terminal single-chain CD3ε T-cell receptor- (TCR)-binding component, a human serum albumin-binding central domain, and an N-terminal BCMA-binding portion. This product, which is in a phase I/II trial for RRMM (NCT04184050), has an extended half-life compared to bispecific formats, a property ascribed to its smaller size and flexibility [76]. Moreover, bispecifics based on myeloma surface antigens other than BCMA have been developed

**145**

*Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma*

as alternative CD3 epitope binding partners. In addition to the aforementioned talquetamab (NCT03399799) [77], these include the CD3xCD38 construct found in GBR 1342 (NCT03309111) [78] and the CD3xFcRH5 design incorporated into

In addition to the BCMAxCD3 bispecific formats noted above, creation of BCMA-targeted constructs directed to receptors on NK cells has been described. Like cytotoxic T-cells, NK cells are known to mediate cytotoxicity through a variety of mechanisms, including granzyme-perforin release and through expression of various apoptosis-inducing ligands [80]. A tri-specific product that binds both BCMA and CD200 on myeloma cells to CD16A on NK cells represents one such drug [81]. Similarly, CTX-4419, which binds BCMA to both NK cell CD16A and p30, has shown initial promise in preclinical models although CD16A binding does not appear to be a requirement for the anti-myeloma activity of this product [82]. Other BCMA-NK cell-engaging antibodies, such as CTX-8573 [83] and AFM26 [84], also

Over the past decade, immune checkpoint blockade has emerged as a principal strategy for new antitumor drug development. This immunotherapeutic approach is based on identification of biomarkers and their cognate ligands that enable the body's immune system to overcome the capacity of tumor cells to evade immune surveillance and elimination, as well as on the design of mAbs to block these interactions. In its most successful application to date, discoveries made concerning the roles played in this process by cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), the first member of this class to serve as a clinical target, and the programmed death (PD) receptor, have given momentum to this innovative line of

Costimulatory signals resulting from interaction of CD28 on the surface of T-cells with its CD80 (B7–1) ligand on antigen-presenting cells play an important role in activating T-cells. CTLA-4, expressed on the T-cell plasma membrane, competes with CD80-CD28 binding to downregulate T-cell activation and thus represents an important mechanism that suppresses immune responses and, as a consequence, enables tumor cells to evade detection. CTLA-4-directed mAbs, by competing with the CD80-CD28 interaction, enhance the ability of T-cells to generate an antitumor response. This strategic approach was successfully applied to the immunotherapy of advanced melanoma by the anti-CTLA-4 mAb ipilimumab, which was approved by the FDA in 2011 and has been extended since to include a number of other solid tumors [86]. However, the drug has shown less than impressive results in hematologic cancers, such as acute myeloid leukemia [87]. One trial (NCT02681302) of ipilimumab combined with nivolumab that included both lymphoma and MM patients is currently active but so far only preliminary efficacy

Binding of PD-1, expressed on the surface of T-cells, to PD-L1 or PD-L2 on tumor cells inhibits cytotoxic T lymphocyte proliferation and cytokine secretion while also causing an increase in the T regulatory cell population. These combined effects produce immune tolerance, enabling unrestrained tumor cell growth and survival [89]. Since 2014, the FDA has approved three PD-1 inhibitors – pembrolizumab (Keytruda®), nivolumab (Opdivo®), and cemiplimab (Libtayo®) and three PD-L1 blockers – avelumab (Bavencio®), durvalumab (Imfinzi®), and atezolizumab (Tecentriq®). Pembrolizumab, the first to be approved and the most versatile member of the checkpoint blocker group, has been approved for

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

have shown some potential as RRMM therapies.

**6. Immune checkpoint inhibitors**

attack on a variety of tumor types [85].

and toxicity data have been reported [88].

BFCR4350A (NCT03275103) [79].

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

as alternative CD3 epitope binding partners. In addition to the aforementioned talquetamab (NCT03399799) [77], these include the CD3xCD38 construct found in GBR 1342 (NCT03309111) [78] and the CD3xFcRH5 design incorporated into BFCR4350A (NCT03275103) [79].

In addition to the BCMAxCD3 bispecific formats noted above, creation of BCMA-targeted constructs directed to receptors on NK cells has been described. Like cytotoxic T-cells, NK cells are known to mediate cytotoxicity through a variety of mechanisms, including granzyme-perforin release and through expression of various apoptosis-inducing ligands [80]. A tri-specific product that binds both BCMA and CD200 on myeloma cells to CD16A on NK cells represents one such drug [81]. Similarly, CTX-4419, which binds BCMA to both NK cell CD16A and p30, has shown initial promise in preclinical models although CD16A binding does not appear to be a requirement for the anti-myeloma activity of this product [82]. Other BCMA-NK cell-engaging antibodies, such as CTX-8573 [83] and AFM26 [84], also have shown some potential as RRMM therapies.

#### **6. Immune checkpoint inhibitors**

*Monoclonal Antibodies*

arm for their respective targets [64].

chains and targeted myeloma cell BCMA.

myeloma-based trial (NCT03486067) [72].

therapeutically relevant properties of constructs may be fine-tuned to optimization by altering biodistribution characteristics and the relative binding affinities of each

Amgen's proprietary BiTE® platform represents an innovative subclass of T-BsAb in which tandem single-chain variable fragments (scFvs) provide the crosslink [65]. The first successful application of BiTE® technology was the CD3-CD19 cross-linking construct blinatumomab (Blincyto®), which was approved by the FDA in 2014 for Philadelphia chromosome-negative B-cell precursor acute lymphocytic leukemia (B-cell ALL). Although a single trial (NCT03173430) of blinatumomab in RRMM patients had to be terminated because of "slow patient accrual", the majority of myeloma-related work using BiTE® constructs have been based on recombinant antibodies designed to cross-link surface tumor-specific T-cell CD3ζ

Initial results with the BCMAxCD3 BiTE® product AMG 420 (BI-836909), which was accorded fast-track status by the FDA in 2018, showed an ORR of 31% in 42 RRMM patients, including seven of ten patients refractory to at least two lines of therapy who received the maximum tolerated dose of 400 μg/day. Infections and polyneuropathy were the most serious adverse events noted in this trial. Cytokine release syndrome (CRS; cytokine storm), predominantly grade 1, was observed in 38% of patients in the study [66, 67]. Monotherapy with AMG 701, a related BiTE® construct with a longer serum half-life than AMG 420, currently is the focus of a phase I trial (NCT03287908) for RRMM. Data generated in a preclinical investigation suggests that future consideration of a trial of AMG 701 in combination with an immunomodulator may be warranted [68]. In addition, two other BCMAxCD3 bispecific antibodies from Regeneron, REGN5458 (NCT03761108) and REGN5459 (NCT04083534), are in phase I RRMM studies. Preliminary data on the first three

Following favorable safety results in a monkey model [70], two phase I RRMM clinical trials of the BCMAxCD3 bispecific teclistamab (JNJ-64007957) have been initiated. In addition to a dose-escalation study (NCT03145181), this agent has been incorporated into a trial (NCT04108195) that includes subcutaneous daratumumab and talquetamab (JNJ-64407564), a CD3xGPRC5D bispecific construct. Another BCMAxCD3 formatted product under scrutiny for RRMM is PF-06863135 (PF-3135) (NCT03269136), the result of hinge-mutation engineering of an IgG2a backbone [71]. CC-93269, a T-cell engager whose arms bind in a 2 + 1 arrangement, monovalently to CD3ε and bivalently to BCMA, is another member of this class in a

TNB-383B, a BCMAxCD3 T-BsAb resulting from collaboration between Tenebio and Abbvie and designated as an orphan drug by the FDA, differs from other drugs in this class in that its structure consists of a single immunoglobulin light chain and two variable heavy chains. The product, which recently began a phase I trial for RRMM (NCT03933735), is noteworthy for its strong T-cell activation kinetics and low affinity anti-CD3 arm, which results in reduced release of cytokines while retaining high cytotoxicity toward myeloma cells [73]. A number of other bispecific antibodies have exhibited promise for RRMM in preclinical work. These include TNB-381 M [74], FPA-151 [74], EM801 [48], and AP163 [75]. HPN217, developed by Harpoon Therapeutics, is a tri-specific antibody possessing three binding domains in a single chain – a C-terminal single-chain CD3ε T-cell receptor- (TCR)-binding component, a human serum albumin-binding central domain, and an N-terminal BCMA-binding portion. This product, which is in a phase I/II trial for RRMM (NCT04184050), has an extended half-life compared to bispecific formats, a property ascribed to its smaller size and flexibility [76]. Moreover, bispecifics based on myeloma surface antigens other than BCMA have been developed

patients treated with the former agent have been reported [69].

**144**

Over the past decade, immune checkpoint blockade has emerged as a principal strategy for new antitumor drug development. This immunotherapeutic approach is based on identification of biomarkers and their cognate ligands that enable the body's immune system to overcome the capacity of tumor cells to evade immune surveillance and elimination, as well as on the design of mAbs to block these interactions. In its most successful application to date, discoveries made concerning the roles played in this process by cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), the first member of this class to serve as a clinical target, and the programmed death (PD) receptor, have given momentum to this innovative line of attack on a variety of tumor types [85].

Costimulatory signals resulting from interaction of CD28 on the surface of T-cells with its CD80 (B7–1) ligand on antigen-presenting cells play an important role in activating T-cells. CTLA-4, expressed on the T-cell plasma membrane, competes with CD80-CD28 binding to downregulate T-cell activation and thus represents an important mechanism that suppresses immune responses and, as a consequence, enables tumor cells to evade detection. CTLA-4-directed mAbs, by competing with the CD80-CD28 interaction, enhance the ability of T-cells to generate an antitumor response. This strategic approach was successfully applied to the immunotherapy of advanced melanoma by the anti-CTLA-4 mAb ipilimumab, which was approved by the FDA in 2011 and has been extended since to include a number of other solid tumors [86]. However, the drug has shown less than impressive results in hematologic cancers, such as acute myeloid leukemia [87]. One trial (NCT02681302) of ipilimumab combined with nivolumab that included both lymphoma and MM patients is currently active but so far only preliminary efficacy and toxicity data have been reported [88].

Binding of PD-1, expressed on the surface of T-cells, to PD-L1 or PD-L2 on tumor cells inhibits cytotoxic T lymphocyte proliferation and cytokine secretion while also causing an increase in the T regulatory cell population. These combined effects produce immune tolerance, enabling unrestrained tumor cell growth and survival [89]. Since 2014, the FDA has approved three PD-1 inhibitors – pembrolizumab (Keytruda®), nivolumab (Opdivo®), and cemiplimab (Libtayo®) and three PD-L1 blockers – avelumab (Bavencio®), durvalumab (Imfinzi®), and atezolizumab (Tecentriq®). Pembrolizumab, the first to be approved and the most versatile member of the checkpoint blocker group, has been approved for

17 different indications, many as front-line therapy for solid tumors ranging from melanoma to small-cell lung cancer to metastatic Merkel cell carcinoma [90]. In 2017, the FDA in an unprecedented move approved pembrolizumab for the treatment of solid tumors having a microsatellite instability (mismatched repair


**147**

*Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma*

deficiency). Known as a tissue agnostic approach to cancer diagnosis and treatment, this marked the first drug approval based on a specific biomarker instead of on the

In terms of hematologic malignancies, pembrolizumab has been approved for treatment of Hodgkin's lymphoma while both pembrolizumab and nivolumab have been approved for primary mediastinal large B-cell lymphoma (PMBCL). While studies of checkpoint inhibitors in both chronic and acute leukemias generally have been disappointing [87], work in the area of MM has shown some degree of efficacy but major issues concerning toxicity have arisen. Following favorable results in early phase trials [92, 93], pembrolizumab/dexamethasone was included in two phase III trials with and without the immunomodulators lenalidomide (NCT02579863— KEYNOTE-185; NDMM) and pomalidomide (NCT02576977—KEYNOTE-183; RRMM). However, in July 2017, the FDA placed clinical holds on both trials due to the higher risk of death in the cohorts receiving the PD-1 blocker [94]. This suspension soon was expanded to include partial or full holds on all myeloma trials using combinations of immunomodulators and checkpoint inhibitors, an action that later was reversed in the case of three myeloma trials that employed nivolumab (NCT03023527, NCT01592370, and NCT02612779); however, no data have been forthcoming for these resumed studies. At this point, any future role that checkpoint inhibitor-immunomodulator combinations may play in MM therapy is very much in a state of flux [95]. Other checkpoints that may serve as targets for MM but for which only limited preclinical or clinical studies are currently available include killer-cell immunoglobulin-like receptors (KIR) [96], CD47 [97], LAG3 [98], TIGIT [99, 100], and TIM-3 [101]. **Table 1** contains a partial list of checkpoint inhibitors

CD138 (syndecan-1), which is overexpressed in MM [107], is the target of indatuximab ravtansine (BT-062), an ADC whose anti-CD138 mAb is linked to a cytotoxic microtubule destabilizing maytansinoid. This agent has been studied in RRMM both in combination with immunomodulators (NCT01638936) and as a single agent (NCT01001442 and NCT00723359). The 34 patients (median 5 prior therapies) in the monotherapy study who received a multi-dose regimen showed a median PFS of three months and median overall survival (OS) of 26.7 months while diarrhea and fatigue were the most commonly reported adverse events [108]. In addition, an anti-CD138 mAb, known as mAb 1610, has shown some potential

CD74 plays a key role as a chaperone, enabling the proper folding and trafficking of MHC Class II proteins in antigen-presenting cells. In addition, this type II transmembrane protein activates the NFκB signaling pathway following the binding of its intracellular domain to macrophage migration inhibitory factor (MIF) and translocation to the nucleus where it induces proliferation and survival, especially in B-cells. Elevated expression of CD74 in B cell malignancies, such as non-Hodgkin's lymphomas and MM, has made this an attractive target for these types of cancer [110]. STRO-001, which has received Orphan Drug status from the FDA, is an anti-CD74 ADC in which an aglycosylated human IgG1 antibody is conjugated to a maytansinoid linker-warhead. A phase I trial (NCT03424603) of STRO-001 in B-cell malignancies, including MM, recently was initiated [111]. Two other CD74-targeting agents, milatuzumab and its doxorubicin-linked ADC, that had been under study in MM, both have been

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

tissue or organ of origin [91].

currently in clinical trials for MM.

**7. Additional mAbs and their targets**

anti-myeloma promise in a preclinical study [109].

dropped from further consideration.

#### **Table 1.**

*Selected active trials of checkpoint inhibitors in MM.*

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

*Monoclonal Antibodies*

**PD-1 Inhibitors**

**PD-L1 Inhibitors** NCT02431208 [105, 106] Trial Start:

**CD47 Inhibitors**

**LAG-3 and TIGIT Inhibitors**

*Trial start date on or after July 1, 2017, unless otherwise noted.*

*Selected active trials of checkpoint inhibitors in MM.*

7/22/15

**Trial ID [reference] N Trial title**

NCT03168438 [103] 20 NY-ESO-1ᶜ

17 different indications, many as front-line therapy for solid tumors ranging from melanoma to small-cell lung cancer to metastatic Merkel cell carcinoma [90]. In 2017, the FDA in an unprecedented move approved pembrolizumab for the treatment of solid tumors having a microsatellite instability (mismatched repair

NCT03848845 [102] 40 A phase I/II single arm open-label study to explore safety and

NCT04361851 33 Phase II study of daratumumab-pembrolizumab for multiple

multiple myeloma NCT03782064 25 A phase II trial of vaccination with dendritic cell (DC)/myeloma

multiple myeloma NCT03292263 [104] 30 Autologous stem cell transplantation with nivolumab in patients with multiple myeloma NCT04119336 50 A phase II study of nivolumab in combination with ixazomib,

multiple myeloma NCT03194867 109 A phase I/II study to evaluate safety, pharmacokinetics and

NCT03111992 26 Phase I/Ib, multi-center, open-label, study of single agent CJM112

cell transplantation)

multiple myeloma

NCT03530683 156 A phase Ia/Ib dose escalation and expansion trial of TTI-622

NCT04150965 104 A phase I/II assessment of combination immuno-oncology

(BMS-986207)

myeloma

NCT03910439 30 A phase II pilot study of avelumab in combination with

myeloma (DREAMM 4) NCT03506360 41 Phase II trial of pembrolizumab, ixazomib, and dexamethasone for relapsed multiple myeloma

clinical activity of GSK2857916 administered in combination with pembrolizumab in subjects with relapsed/refractory multiple

259T alone and in combination with pembrolizumab for

fusions in combination with nivolumab in patients with relapsed

cyclophosphamide, and dexamethasone in relapsed and refractory

efficacy of isatuximab in combination with cemiplimab in patients

(anti-IL17A mAb), and spartalizumab (PDR001) in combination with LCL161 (SMAC mimetic) or CJM112 in patients with

immunomodulatory drug and/or daratumumab in patients with multiple myeloma (relapsed/ refractory and post-autologous stem

hypofractionated radiotherapy in patients with relapsed refractory

in patients with advanced relapsed or refractory lymphoma or

drugs elotuzumab, anti-LAG-3 (BMS-986016) and anti-TIGIT

with relapsed/refractory multiple myeloma

relapsed and/or refractory multiple myeloma

300 A phase Ib study of the safety and pharmacokinetics of atezolizumab alone or in combination with an

myeloma patients with ≥ three prior lines of therapy

**146**

**Table 1.**

deficiency). Known as a tissue agnostic approach to cancer diagnosis and treatment, this marked the first drug approval based on a specific biomarker instead of on the tissue or organ of origin [91].

In terms of hematologic malignancies, pembrolizumab has been approved for treatment of Hodgkin's lymphoma while both pembrolizumab and nivolumab have been approved for primary mediastinal large B-cell lymphoma (PMBCL). While studies of checkpoint inhibitors in both chronic and acute leukemias generally have been disappointing [87], work in the area of MM has shown some degree of efficacy but major issues concerning toxicity have arisen. Following favorable results in early phase trials [92, 93], pembrolizumab/dexamethasone was included in two phase III trials with and without the immunomodulators lenalidomide (NCT02579863— KEYNOTE-185; NDMM) and pomalidomide (NCT02576977—KEYNOTE-183; RRMM). However, in July 2017, the FDA placed clinical holds on both trials due to the higher risk of death in the cohorts receiving the PD-1 blocker [94]. This suspension soon was expanded to include partial or full holds on all myeloma trials using combinations of immunomodulators and checkpoint inhibitors, an action that later was reversed in the case of three myeloma trials that employed nivolumab (NCT03023527, NCT01592370, and NCT02612779); however, no data have been forthcoming for these resumed studies. At this point, any future role that checkpoint inhibitor-immunomodulator combinations may play in MM therapy is very much in a state of flux [95]. Other checkpoints that may serve as targets for MM but for which only limited preclinical or clinical studies are currently available include killer-cell immunoglobulin-like receptors (KIR) [96], CD47 [97], LAG3 [98], TIGIT [99, 100], and TIM-3 [101]. **Table 1** contains a partial list of checkpoint inhibitors currently in clinical trials for MM.

### **7. Additional mAbs and their targets**

CD138 (syndecan-1), which is overexpressed in MM [107], is the target of indatuximab ravtansine (BT-062), an ADC whose anti-CD138 mAb is linked to a cytotoxic microtubule destabilizing maytansinoid. This agent has been studied in RRMM both in combination with immunomodulators (NCT01638936) and as a single agent (NCT01001442 and NCT00723359). The 34 patients (median 5 prior therapies) in the monotherapy study who received a multi-dose regimen showed a median PFS of three months and median overall survival (OS) of 26.7 months while diarrhea and fatigue were the most commonly reported adverse events [108]. In addition, an anti-CD138 mAb, known as mAb 1610, has shown some potential anti-myeloma promise in a preclinical study [109].

CD74 plays a key role as a chaperone, enabling the proper folding and trafficking of MHC Class II proteins in antigen-presenting cells. In addition, this type II transmembrane protein activates the NFκB signaling pathway following the binding of its intracellular domain to macrophage migration inhibitory factor (MIF) and translocation to the nucleus where it induces proliferation and survival, especially in B-cells. Elevated expression of CD74 in B cell malignancies, such as non-Hodgkin's lymphomas and MM, has made this an attractive target for these types of cancer [110]. STRO-001, which has received Orphan Drug status from the FDA, is an anti-CD74 ADC in which an aglycosylated human IgG1 antibody is conjugated to a maytansinoid linker-warhead. A phase I trial (NCT03424603) of STRO-001 in B-cell malignancies, including MM, recently was initiated [111]. Two other CD74-targeting agents, milatuzumab and its doxorubicin-linked ADC, that had been under study in MM, both have been dropped from further consideration.

Another conjugate linked to a maytansine derivative, the anti-CD56 ADC lorvotuzumab mertansine (IMGN901; BB-10901), had been the focus of a phase I trial in CD56-positive RRMM patients (NCT00346255) but insufficient efficacy and dose-related toxicity reportedly led to discontinuation of further studies of this agent [112, 113]. Other mAbs that have been dropped from further consideration in MM following demonstration of only modest efficacy and/or unacceptable toxicity in trials include the following (target in parentheses): dacetuzumab and lucatumumab (CD40); F50067 (CXCR-4); AVE1642 and figitumumab (IGF-R1); IPH 2101 (KIR); PAT-SM6 (GRP-78); BI 505 (intercellular adhesion molecule-1, ICAM-1), and siltuximab (IL-6).
