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L. Rasche et al.
Figure 1. Mode of action illustrated for antibody-drug conjugates, T-cell-engaging antibodies and chimeric antigen receptor T cells. MMAF: monomethyl auristatin F; MM: multiple myeloma; BCMA: B-cell maturation antigen; TCR: T-cell receptor.
FOR-46
The MMAF-coupled ADC FOR-46, currently undergo- ing evaluation in a phase I, dose-escalation study (NCT03650491), is directed against the complement reg- ulatory protein CD46. This ADC targets a tumor-specific epitope of CD46 and efficiently induces macropinocyto- sis.23
HDP-101
The cytotoxic potential of the ADC HDP-101 is based on a synthetic version of the Amanita phalloides toxin amanitin, a specific inhibitor of RNA polymerase II.24 This inhibition of gene transcription and protein synthesis is cell cycle- independent, an important property given that in many cases a large fraction of MM cells are not proliferating. This rare property may be a clinically important characteristic of HDP-101. Due to its chromosomal location, RNA poly- merase II is frequently co-deleted with TP53 in del(17p). MM cells with this high-risk feature are therefore likely to be highly sensitive to HDP-101. Promising preclinical safe- ty and activity data have been reported25 and a first-in- human, phase I, dose escalation and expansion study for RRMM patients is planned for 2021.26
Bispecific antibodies
Bispecific TCE represent another approach to treating MM, utilizing the high cytolytic activity of T cells. While one arm binds to a plasma cell or B-cell lineage associated antigen, a second arm recruits T cells via the CD3 domain, thereby bringing T cells in close proximity to MM cells, ultimately leading to granzyme and perforin exocytosis and apoptosis of the target cell (Figure 1).
AMG 420
Proof-of-principle of the validity of this strategy was recently provided by a study on AMG 420, a bispecific T- cell-engager (BiTE®) targeting BCMA.27 In a dose-escalating phase I study in RRMM,27 the ORR was 70% at a dose of 400 mg/day and some patients responded for more than 1 year. In a single-center study, the median PFS was 23.5 months for responders (n=10).28 Like the CD19xCD3 BiTE® blinatumomab, AMG 420 has a short half-life with rapid elimination from the circulation. Continuous infusion over weeks was therefore necessary, causing substantial incon- venience to patients. In light of the multiple other TCE variants with longer half-lives under clinical investigation, the manufacturer did not pursue further development of AMG 420. Numerous abstracts on TCE were presented at the ASH annual meeting in 2020, and initial clinical data on at least seven new TCE were reported (Table 2).
Teclistamab
Teclistamab (JNJ-64007957) is a humanized bispecific IgG4 antibody that binds to BCMA on target cells and CD3 on T cells (BCMA x CD3). Currently being evaluated in an ongoing phase I study, teclistamab is available in both intravenous and subcutaneous formulations, and is admin- istered on a weekly schedule. Updated results from 149 patients, presented at ASH in 2020, showed a favorable safety profile and promising efficacy.29 Although cytokine release syndrome (CRS) was seen in more than half of the patients (55% in the intravenous group, and 64% in the subcutaneous group), no grade 3 CRS was recorded, and nodose-limitingtoxicitywasreportedattherecommend- ed phase II dose of 1500 mg/kg subcutaneously. The ORR was 73%, with 55% of the patients achieving a very good partial response or better at the recommended phase II
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haematologica | 2021; 106(10)