Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells

Kinneer, Krista; Flynn, Matt; Thomas, Sabu; Meekin, John; Varkey, Reena; Xiao, Xiaodong; Zhong, Haihong; Breen, Shannon; Hynes, Paul G.; Fleming, Ryan; Bezabeh, Binyam; Chen, Cui Tracy; Wetzel, Leslie; Chen, Ruoyan; Dimasi, Nazzareno; Tai, Yu‐Tzu; Anderson, Kenneth C.; Herbst, Ronald; Howard, Philip W.; Hurt, Elaine M.; Tice, David A.

doi:10.1038/s41375-018-0278-7

Cited by 57 publications

(61 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this case, drugs that inhibit γsecretase could enhance the efficacy of BCMA-targeted therapy by reducing shedding of BCMA from the cell surface and subsequent interference of BCMA-targeted therapies by sBCMA [20,21,38]. An additional approach could be to use anti-BCMA monoclonal antibodies (mAbs) with higher specificity for membrane-bound BCMA than sBCMA [39]. As it is currently unclear whether changes in membranebound or sBCMA levels during therapy could alter the longterm efficacy of anti-BCMA therapies, additional investigation into the relationship between baseline sBCMA and response to BCMA-directed therapies is warranted.…”

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

View full text Add to dashboard Cite

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

show abstract

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Before conjugation these Fabs were reduced again with two‐fold equivalents of tris(2‐carboxyethyl)phosphine (TCEP) at 37 °C with shaking for 1 h. The Fabs prepared using transient expression were reduced only once using two‐fold equivalents of TCEP at 37 °C with shaking for 1 h. The reduced Fabs were then used for conjugation using two‐fold equivalents of SG3710 prepared in 100 % dimethyl sulfoxide (10 % final DMSO concentration, Sigma–Aldrich). The conjugation was carried out with shaking at room temperature for 1 h. Trastuzumab site‐specifically conjugated to two PBDs (SG3249) was prepared and characterized as described previously …”

Section: Methodsmentioning

confidence: 99%

“…The dual-maleimide PBD SG3710 [28] was synthesized using startingm aterial from tesirine (SG3249, Figure 1a), [29,30] aP BD payload used in several ADCs in clinical development. [31][32][33][34] SG3710 contains two maleimide-(polyethylene glycol) 8 -valinealanine-para-aminobenzoic acid linkers at each of the two sym-metricalN 10 positions of the PBD (Figure 1b). The warhead (i.e.,t he sequence-selective DNA minor-groove cross-linker) of SG3710 is SG3199 (depicted in blue in Figure1), [35] which is also the warhead of tesirine (SG3249).…”

Section: Structural Characteristics Of Sg3710mentioning

confidence: 99%

“…The conjugation was carried out with shaking at room temperature for 1h.T rastuzumab sitespecifically conjugated to two PBDs (SG3249) was prepared and characterized as described previously. [17,34] Purification of the FDCs:A fter conjugation the FDCs were purified using semi-preparative hydrophobic interaction chromatography (HIC) to remove free SG3710 and other contaminants. HIC was carried out using 5mLH iTrap Butyl HP column (GE Healthcare) and an AKTAP ure system (GE Healthcare).…”

Section: Antibodies and Fabsmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Disulfide Bond Rebridged Fab–Drug Conjugates Prepared Using a Dual Maleimide Pyrrolobenzodiazepine Cytotoxic Payload

Ruddle

Fleming

et al. 2019

ChemMedChem

Self Cite

View full text Add to dashboard Cite

We describe the characterization of antigen binding fragments (Fab)–drug conjugates prepared using a dual maleimide pyrrolobenzodiazepine dimer cytotoxic payload (SG3710). Pyrrolobenzodiazepine dimers, which are DNA cross‐linkers, are a class of payloads used in antibody–drug conjugates (ADCs). SG3710 was designed to rebridge two adjacent cysteines, such as those that form the canonical interchain disulfide bond between the light and heavy chain in Fab fragments. The rebridging generated homogenous Fab conjugates, with a drug‐to‐Fab ratio of one, as demonstrated by the preparation of rebridged Fabs derived from the anti‐HER2 trastuzumab antibody and from a negative control antibody both prepared using recombinant expression and papain digestion. The resulting anti‐HER2 trastuzumab Fab‐rebridged conjugate retained antigen binding, was stable in rat serum, and demonstrated potent and antigen‐dependent cancer cell‐killing ability. Disulfide rebridging with SG3710 is a generic approach to prepare Fab–pyrrolobenzodiazepine dimer conjugates, which does not require the Fabs to be engineered for conjugation. Thus, SG3710 offers a flexible and straightforward platform for the controlled assembly of pyrrolobenzodiazepine dimer conjugates from any Fab for oncology applications.

show abstract

“…The significance of BAFF and APRIL, and their receptors BCMA and TACI, in the growth and survival of myeloma cells suggests that these paired ligands and receptors can be targets for the development of new therapies against MM. Indeed, a number of BCMA-targeting immunotherapies, including anti-BCMA antibody-drug conjugate [65][66][67][68], anti-BCMA bi-specific T cell engager (BiTE) [69,70], and BCMAtargeting chimeric antigen receptor T cells [71][72][73][74][75][76], have been developed and are at different stages of preclinical and clinical development for the treatment of resistant/relapsed MM and they have yielded promising results. However, the variable density of BCMA on MM cells in different patients and the propensity of target escape after initial BCMA-targeting immunotherapy may compromise therapeutic efficacy.…”

Section: Targeting Taci In Immunotherapy Against MMmentioning

confidence: 99%

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

Lam

2020

Cancers

View full text Add to dashboard Cite

Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM.

show abstract

Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells

Cited by 57 publications

References 14 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Characterization of Disulfide Bond Rebridged Fab–Drug Conjugates Prepared Using a Dual Maleimide Pyrrolobenzodiazepine Cytotoxic Payload

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

Contact Info

Product

Resources

About