Correction to: Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study

Abstract B cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). We here investigated the anti-MM activity of J6M0-mcMMAF (GSK2857916), a humanized and afucosylated anti-BCMA antibody-drug conjugate (ADC) via uncleavable linker. This novel antagonist anti-BCMA antibody shows binding against all CD138-expressing MM cell lines (n=13) and patient MM cells (n=18), confirming universal BCMA expression on the surface of myeloma cells. Real-time qRT-PCR also showed significantly upregulated BCMA mRNA in CD138+ cells purified from MM patients vs. normal donors (p < 0.03). In contrast, BCMA is undetectable in CD138-negative cells from MM patients (n=3). J6M0-mcMMAF strongly blocks cell growth and induces caspase 3-dependent apoptosis in both drug-sensitive and -resistant MM cell lines and patient CD138+ MM cells, alone and in co-culture with BMSCs. In contrast, an isotype control antibody-drug conjugate (iso-mcMMAF) had no effect on viability of ANBL6 MM cells, alone or cocultured with BMSC. J6M0-mcMMAF specifically induces cell death in CD138-positive patient MM cells but not CD138-negative cells, demonstrating the minimal bystander killing against surrounding BCMA-negative cells. J6M0-mcMMAF completely blocks colony formation of MM cell lines (n=6) via induction of G2/M arrest, followed by apoptosis. This ADC does not affect viability of BCMA-negative NK, PBMC, and BMSCs, cultured alone or together, confirming its specific targeting of BCMA-positive MM cells. J6M0-mcMMAF, which has enhanced Fc-receptor binding due to afucosylation, significantly improved autologous antibody-dependent cellular cytotoxicity (ADCC) potency and maximum MM cell lysis against MM patient cells (n=5), when compared to J6M0 with normal Fc. Such augmented ADCC and maximum patient MM cell lysis by J6M0-mcMMAFis more pronounced in the autologous setting vs. the allogenic setting where MM cells and healthy donor effectors were used. Pretreatment of PBMC effector cells with lenalidomide further increased J6M0-mcMMAF-induced ADCC against MM cells in the presence or absence of BMSC. The in vivo efficacy of J6M0-mcMMAF was evaluated in murine subcutaneous xenograft models using NCI-H929 and OPM2 cells, as well as in NK-deficient SCID-beige mice with diffuse human MM bone lesions using MM1Sluc cells. Administration of J6M0-mcMMAF at 4 mg/kg (q3d x 4, ip) completely eliminated NCI-H929 and OPM2 xenograft tumors in all mice which remained tumor-free until the termination of studies at 60 and 100 days, respectively. In the MM1Sluc bone marrow dissemination model, J6M0-mcMMAF eradicates detectable tumors after 2 doses at 0.4 mg/kg (q3d x 9, ip), which resulted in extended survival (p<0.0001) and no weight loss of mice following 120 days. J6M0 treatment, although less effective than J6M0-mcMMAF, also had significantly prolonged survival (p<0.03) and diminished tumor burden when compared with control vehicle and isotype-treated groups, indicating a potential role of macrophage-mediated phagocytosis. Indeed, J6M0-mcMMAF recruits macrophage and mediates phagocytosis of target MM cells. Taken together, our studies show that J6M0-mcMMAF potently and selectively induce direct and indirect killing of MM tumor cells both in vitro and in vivo, providing a very promising next-generation immunotherapeutic in this cancer. Disclosures: Tai: Onyx: Consultancy. Mayes:GlaxoSmithKline: Employment. Craigen:GlaxoSmithKline: Employment. Gliddon:GlaxoSmithKline: Employment. Smothers:GlaxoSmithKline: Employment. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

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Preclinical Development of a Bcma Targeting Antibody-Drug Conjugate with Novel Payload for Multiple Myeloma Therapy

Blood ◽

10.1182/blood-2019-132080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5623-5623

Author(s):

Andrew Hau ◽

Tong Zhu ◽

Rengang Wang ◽

Megan Lau ◽

Lingna Li ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Antibody Drug Conjugate ◽

Preclinical Development ◽

Employment Equity ◽

Drug Conjugate ◽

Equity Ownership ◽

Anti Tumor Activity ◽

Antibody Drug

BCMA (B-cell maturation antigen) is an integral membrane protein that belongs to the TNF receptor family with expression restricted to B cell lineage cells. The RNA is near universally detected in multiple myeloma (MM) cells and the protein is expressed on the surface of malignant plasma cells from patients with MM. In contrast, BCMA expression in normal tissues is very limited, making BCMA a promising target for antibody-drug conjugate (ADC) therapy. We have developed a BCMA-targeting ADC, employing a fully human anti-BCMA monoclonal antibody (mAb) identified from Sorrento's G-MAB antibody library, which was conjugated using proprietary Concortis linker-Duo 5.2 toxin technology resulting in BCMA-077 ADC. The mAb has a unique binding profile for BCMA and demonstrated strong preferential binding for BCMA-overexpressing cells but showed much less binding to lower BCMA-expressing cells. This property allows for more selective binding of the ADC on high BCMA-expressing cells, which are usually tumor cells while sparing low BCMA-expressing normal cells. In addition, we modified the Duo 5.2 payload decreasing the potency of the unconjugated toxin while retaining activity when conjugated to the mAb. The resulting ADC, BCMA-024, was compared to BCMA-077 using in vitro assays, including binding, internalization and cytotoxicity against tumor cell lines. The two ADCs exhibited strong activity and no difference in cytotoxic potency evident. The toxicity of the payload derivative was evaluated in a rodent model and it was found to be well tolerated not showing toxicity at a dose 10 times higher than the lethal dose of the parental toxin. Both ADCs carrying either the parental Duo 5.2 toxin or the derivative toxin payload were evaluated in vivo for anti-tumor activity in three different multiple myeloma xenograft models using different dose regimens. The data showed that both ADCs demonstrated potent BCMA-dependent in vivo anti-tumor activity in all xenograft BCMA-positive tumor models. The PK of the parental anti-BCMA mAb was investigated in non-human primates (NHP) and the parameters indicated a T1/2 of about 10 days. The GLP toxicity studies are ongoing. Our BCMA-ADCs have shown favorable anti-tumor activities combined with good safety profiles resulting in an expanded therapeutic window. The data make BCMA-077 and BCMA-024 promising candidates for continued preclinical development. Based on the totality of our preclinical data, we anticipate selecting a BCMA ADC clinical candidate for the treatment of multiple myeloma. Disclosures Hau: Concortis Biotherapeutics: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Wang:Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Li:Concortis Biotherapeutics: Employment, Equity Ownership. Li:Levena Biopharma: Employment, Equity Ownership. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.

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