BCMA-Targeting Antibody-Drug Conjugates in Multiple Myeloma

BCMA-Targeting Antibody-Drug Conjugates in Multiple Myeloma: Comparison

Please note this is a comparison between Version 1 by Yuntong Liu and Version 2 by Beatrix Zheng.

Multiple myeloma (MM) is an incurable cancer of the plasma cells. OvIn ther the last twenty years, treatment strategies have evolved toward targeting MM cells—from the shotgun chemotherapy approach to the slightly more targeted approach of disrupting important MM molecular pathways to the immunotherapy approach that specifically targets MM cells based on protein expression. Antibody-drug conjugates (ADCs) are introduced as immunotherapeutic drugs which utilize an antibody to deliver cytotoxic agents to cancer cells distinctively. Recent investigations of ADCs for MM treatment focus on targeting B cell maturation antigen (BCMA), which regulates B cell proliferation, survival, maturation, and differentiation into plasma cells (PCs). Given its selective expression in malignant PCs, BCMA is one of the most promising targets in MM immunotherapy. Compared to other BCMA-targeting immunotherapies, ADCs have several benefits, such as lower price, shorter production period, fewer infusions, less dependence on the patient’s immune system, and they are less likely to over-activate the immune system.

B cell maturation antigen
multiple myeloma
antibody-drug conjugates
Anti-BCMA ADC
drug resistance

1. B Cell Maturation Antigen (BCMA)

B cell maturation antigen (BCMA) was first identified in 1992 on the short arm of chromosome 16 at 16p13.1 in malignant human T-cell lymphoma ^[1][28]. It is a type III transmembrane glycoprotein with 6 conserved cysteines in its extracellular domain. It belongs to the tumor necrosis factor receptor (TNFR) superfamily as TNRSF17 and is primarily present in a perinuclear structure that overlaps the Golgi apparatus, but functional BCMA is also found on the cell surface ^[1][2][3][4][28,29,30,31].

BCMA functions in conjunction with two related TNFR superfamily members, B-cell activation factor receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Their collaboration regulates various aspects of B cell activities, such as proliferation, survival, maturation, and differentiation into plasma cells (PCs) ^[2][3][5][29,30,32]. Upon binding its cognate ligands, BAFF and APRIL, BCMA can activate the NF-kB, Elk-1, p38, or JNK pathways to transduce signals for corresponding functions ^[4][6][7][8][31,33,34,35]. Conversely, a soluble form of BCMA (sBCMA), generated by γ-secretase (GS), neutralizes APRIL as a decoy and hinders the activation of subsequent BCMA pathways ^[9][36]. The sBCMA level has been suggested as a biomarker since it is significantly higher in MM patients compared to healthy individuals, and higher levels are associated with poor prognosis ^[10][11][37,38], MM progression, and poor response to BCMA-targeted therapy ^[11][12][38,39].

Since its discovery, various studies have demonstrated that BCMA is a promising immunotherapeutic target for multiple myeloma. BCMA expression is restrictively found on the surface of plasmablasts and differentiated PCs, with no expression on CD34+ hematopoietic stem cells, naive B cells, memory B cells, and other normal tissue cells ^[13][40]. Furthermore, it has a high expression on the surface of the MM cell and is necessary for the survival of long-lived bone marrow plasma cells ^[14][15][41,42]. Both BCMA mRNA and protein have higher expression in malignant PCs than normal PCs, as validated by multiple gene expression profiling ^[13][16][17][40,43,44] and immunohistochemistry studies ^[13][40]. Moreover, Carpenter et al. ^[13][40] found BCMA cDNA in several hematologic tissues, including blood leukocytes, bone marrow, spleen, lymph node, and tonsil, but no BCMA cDNA in other normal human tissues except for the testis, trachea, and some gastrointestinal organs, where low levels of BCMA cDNA were detected, likely from plasma cells present in lamina propria and Peyer’s patches. These findings indicate BCMA is a desirable therapeutic target.

2. Anti-BCMA ADC

An antibody-drug conjugate (ADC) solves many of the above problems. An ADC comprises three components: a monoclonal antibody against a target, a cytotoxic agent (payload), and a stable linker connecting the two ^[18][19][20][54,55,56]. Since only a small amount of injected antibodies localize to tumor cells, most payloads are highly potent, with cytotoxicity in the picomolar range, often targeting tubulin or causing DNA damage ^[20][21][22][56,57,58]. The linker covalently binds the payload to the antibody and is critical to ADC efficacy, pharmacokinetics, pharmacodynamics, and therapeutic index. A stable linker ensures the release of the cytotoxic drug to target tissue and minimizes toxic effects. On the other hand, an overly strong linker impedes the delivery of the drug. Both cleavable and non-cleavable linkers, which rely on the physiological environment and degradation in endosomes and lysosomes, respectively, have been developed ^[23][24][59,60].

In MM treatment, BCMA is considered one of the most promising targets of ADCs. Following binding to BCMA, the ADC is internalized by endocytosis. The drug is released by cleavage or degradation in endosomes or lysosomes and then causes DNA damage, inhibits transcription, or disrupts microtubules, which leads to apoptosis (Figure 1). The development of anti-BCMA ADCs is an active area of research, and several anti-BCMA ADCs are in various stages of clinical trials (Table 1).

Figure 1.

General mechanism action of an anti-BCMA ADC in myeloma cell. Created with BioRender.com.

Table 1.

Summary of current clinical trials of anti-BCMA ADC.

Drug	Clinical Trial	Prior Lines of Therapy (Median)	N	Results	Most Common AEs	Ref.
Belamaf	DREAMM-1 (NCT02064387), phase I	≥2	73	Dose expansion part (n = 25): ORR 60%, CR 3%, 43% VGPR, 9% PR, mPFS 12 months, mDoR 14.3 months	Nausea, fatigue, thrombocytopenia, anemia, vision blur, chills, dry eye, aspartate aminotransferase increase, pyrexia	^[25]^[26]	[61,62]
Belamaf (2.5 vs. 3.4 mg/kg)	DREAMM-2 (NCT03525678), phase II	≥3	197	ORR 31% vs. 35%, ≥VGPR 19% vs. 24%, mDoR NR vs. 6.2 months, mPFS NR vs. 8.4 months	Keratopathy, thrombocytopenia, anemia, neutropenia	^[27]^[28]^[29]	[63,64,65]
Belamaf vs. Pd	DREAMM-3 (NCT04162210), phase III	≥2	325	ORR 41% vs. 36%, ≥VGPR 25% vs. 8%, mPFS 11.2 months vs. 7 months, does not meet the primary endpoint of PFS, mOS 21.2 months vs. 21.1 months		^[30]^[31]	[66,67]
Belamaf + Pd	ALGONQUIN (NCT03715478), phase I/II	1–5 (3)	60	ORR 88.9%, ≥VGPR 74.1%, mPFS 24.2 months	Keratopathy, blurred vision, fatigue, neutropenia, thrombocytopenia, fever, diarrhea, constipation, dry eye	^[32]	[68]
Belamaf + pembrolizumab	DREAMM-4 (NCT03848845), phasen I/II	3–13 (5)	34	ORR 47%, CR 12%, VGPR 18%, PR 18%, mDoR 8.0 months, mPFS 3.4 months	Keratopathy, blurred vision, thrombocytopenia	^[33]^[34]	[69,70]
Belamaf-containing combinations (e.g., Belamaf + nirogacestat)	DREAMM-5 (NCT04126200), phase I/II	3–10 (4.5)	10	ORR 60%, VGPR 20%, PR 40%	Ocular events	^[35]^[36]	[71,72]
Belamaf + Len + Dex vs. Belamaf + Bortezomib + Dex	DREAMM-6 (NCT03544281), phase I/II	1–11 (3)	45	ORR 78%, ≥VGPR 50%	Keratopathy, blurred vision, dry eye, thrombocytopenia	^[37]	[73]
Belamaf + Bortezomib + Dex vs. Daratumumab + Bortezomib + Dex	DREAMM-7 (NCT04246047), phase III		575 (estimated)
Belamaf + Pd vs. Bortezomib + Pd	DREAMM-8 (NCT04484623), phase III		300 (estimated)
Belamaf + VRd vs. VRd	DREAMM-9 (NCT04091126), phase I		144 (estimated)
MEDI2228	NCT03489525, phase I	2–11	82	ORR 61%, VGPR 24.4%, PR 36.6%, DoR not reached	Photophobia, thrombocytopenia, rash, increased gamma-glutamyltransferase, dry eye, pleural effusion	^[38]	[74]
AMG 224	NCT02561962, phase I	2–11(7)	42	ORR 23%, CR 5%, VGPR 5%, PR 13%, mDoR 14.7 months	Thrombocytopenia, fatigue, nausea, aspartate aminotransderase increase, anemia	^[39]	[75]
HDP-101	NCT04879043, phase I/II	5–16 (11)	4			^[40]	[76]
CC-99712	NCT04036461, phase I		160 (estimated)

Pd: pomalidomide and dexamethasone; Len: lenalidomide; Dex: lexamethasone; VRd: bortezomib, lenalidomide, and dexamethasone; AE: Adverse event; ORR: overall response rate; CR: complete response; VGPR: very good partial response; PR: partial response; mDoR: median duration of response; NR: not reached; mPFS: median progression-free survival; mOS: median overall survival.

2.1. Belantamab Mafodotin

Belamaf (J6M0-mc–MMAF, belantamab mafodotin, GSK2857916) is the most well-studied ADC in myeloma. Its antibody component is an afucosylated IgG1 directed to BCMA (Kd of ~0.5 nM) ^[16][43]. Once it binds BCMA on the MM cell membrane, the entire ADC is internalized and digested in the lysosome, which breaks the non-cleavable maleimidocaproyl (MC) linker and releases the drug monomethyl auristatin F (MMAF). MMAF blocks tubulin polymerization and induces G2-M growth arrest, thus causing caspase 3/7-dependent apoptosis ^[16][43]. MMAF is a synthetic analog of dolastatin, a common drug component in ADCs. Its non-cell-permeable nature reduces the toxicity to healthy cells.

The benefits of Belamaf are not limited to its ability to induce apoptosis directly. The NF-kB signaling pathway essential for MM cell growth and survival is blocked by Belamaf as its specifically engineered anti-BCMA antibody competes with APRIL and BAFF for binding to BCMA ^[16][43]. It is worth noting that blocking BAFF and APRIL can impair the function of immune cells, such as T cells and NK cells, and potentially lead to an increased susceptibility to infections and other diseases ^[41][77]. It was also noted that the afucosylation of its Fc domain substantially enhances the binding affinity to the FcγR (FcγRIIIa) present in effector cells, such as NK cells, monocytes, and macrophages. Consequently, the killing of MM cells is further improved by elevated antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The safety and efficacy results from clinical results supported the approval of Belamaf as a Breakthrough Therapy by the FDA and as a priority medicine (PRIME) by the European Medicines Agency (EMA) in 2017. It was approved by the FDA in 2020 as a monotherapy treatment for R/R MM patients who have received 4 prior therapies including anti-CD38 mAb, PI, and IMiDs.

2.2. MEDI2228

MEDI2228 includes a fully humanized BCMA antibody conjugated to pyrrolobenzodiazepine (PBD) via a protease-cleavable linker. In pre-clinical models, this ADC targets bulk MM cells as well as patient MM progenitor cells that are CD19 + CD138- and kills cells by inducing multiple DNA damage response genes via phosphorylating ATM/ATR kinases, checkpoint kinases 1/2 (CHK1/2), and H2AX regardless of p53 status ^[42][79]. Unlike Belamaf, MEDI2228 preferentially binds to membrane-bound BCMA over sBCMA ^[43][80], which makes it more efficient than Belamaf and means its cytotoxicity is minimally affected by sBCMA levels. MEDI2228 demonstrated impressive single-agent clinical activity in heavily pre-treated MM patients that had received previous immunotherapy. In vitro and in vivo studies suggest that MEDI2228 has a synergistic effect with bortezomib and DNA damage response checkpoint inhibitors ^[44][81]. Furthermore, as MEDI2228 upregulates expression of CD38 and NKG2D ligands on the MM cell surface, it increases NK cell immune activity and restores daratumumab-induced ADCC, supporting the combination of CD38- and BCMA-targeted immunotherapies ^[45][82].

2.3. AMG 224

AMG 224 is composed of an anti-BCMA antibody, the non-cleavable linker 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (MCC), and the cytotoxic agent DM1. DM1, a derivative of the ansamycin antibiotic maytansine, is a tubulin development inhibitor that prevents tumor growth ^[46][83]. Its safety and benefits were proved in the clinical trial in R/R MM patients.

2.4. HDP-101

HDP-101 is another anti-BCMA ADC, but its cytotoxic agent, amanitin, is a new class of payload that impedes the transcription process by inhibiting RNA polymerase II. This reduces cell proliferation and causes cell apoptosis at very low concentrations. In in vitro MM cell models, the picomolar range of HDP-101 was cytotoxic to BCMA+ cells but not BCMA− cells ^[47][84]. In mouse xenograft models, tumor reduction and complete remission were observed depending on the HDP-101 dose. The safety of HDP-101 was further evaluated in nonhuman primates, where only a transient, mild to moderate increase in liver enzymes and lactate dehydrogenase was observed, indicating good tolerability and therapeutic index. Another recent study showed that it suppressed tumor burden in cell lines with a 17p deletion which remains an adverse prognostic factor of MM ^[48][85].

2.5. CC-99712

CC-99712 is an anti-BCMA ADC granted orphan drug designation by the FDA in 2021. Its payload is a non-cleavable maytansinoid. To date, no pre-clinical study has been published concerning this ADC.