MGD011, A CD19 x CD3 Dual-Affinity Retargeting Bi-specific Molecule Incorporating Extended Circulating Half-life for the Treatment of B-Cell Malignancies

Abstract

Purpose: CD19, a B-cell lineage-specific marker, is highly represented in B-cell malignancies and an attractive target for therapeutic interventions. MGD011 is a CD19 x CD3 DART bispecific protein designed to redirect T lymphocytes to eliminate CD19-expressing cells. MGD011 has been engineered with a modified human Fc domain for improved pharmacokinetic (PK) properties and designed to cross-react with the corresponding antigens in cynomolgus monkeys. Here, we report on the preclinical activity, safety and PK properties of MGD011.Experimental Design: The activity of MGD011 was evaluated in several in vitro and in vivo models. PK, safety and pharmacodynamic activity was also assessed in dose-escalation and repeatdose studies of MGD011 administered once weekly in cynomolgus monkeys.Results: MGD011 mediated killing of human B-cell lymphoma lines by human or cynomolgus monkey PBMCs as well as autologous B-cell depletion in PBMCs from both species. MGD011-mediated killing was accompanied by target-dependent T-cell activation and expansion, cytokine release and upregulation of perforin and granzyme B. MGD011 demonstrated antitumor activity against localized and disseminated lymphoma xenografts reconstituted with human PBMCs. In cynomolgus monkeys, MGD011 displayed a terminal half-life of 6.7 days; once weekly intravenous infusion of MGD011 at doses up to 100 mg/kg, the highest dose tested, was well tolerated and resulted in dose-dependent, durable decreases in circulating B cells accompanied by profound reductions of B lymphocytes in lymphoid organs.Conclusions: The preclinical activity, safety and PK profile support clinical investigation of MGD011 as a therapeutic candidate for the treatment of B-cell malignancies.

LAG3 (CD223) as a cancer immunotherapy target

“…Similarly, MacroGenics has developed a bispecific agent that simultaneously binds LAG3 and PD1 (MGD013), generated using their Dual‐Affinity Re‐Targeting (DART) platform, this agent is currently under clinical testing. This technology, previously used for the generation of a CD19/CD3 DART protein designed to redirect T cells to eliminate CD19‐expressing cells in hematological malignancies, covalently links two polypeptide chains between the variable domains of the two antibodies by a disulfide bridge, with a short linker connecting the binding domains to promote heterodimerization . Several other companies are developing their own novel reagents for targeting LAG3, attesting to the broad interest in the LAG3 pathway.…”

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

“…The efficacies (maximal % lysis) of AFM11 and blinatumomab were comparable at E/T > 2; however, a higher concentration was required for the latter to achieve the maximal lysis. Duvortuxizumab was also shown to be more potent than blinatumomab, and EC 50 against Raji/GF cell line using human T lymphocytes at E:T ratio of 10:1 was 0.17 pM (0.019 ng/mL), compared with 7 pM (0.38 ng/mL) for blinatumomab after 24 h incubation [67]. While the potency of these bsAbs varies rather widely, it should be noted that the affinity is not likely to be the only contributor to these differences in potency; differences in the structures and epitopes of these bsAbs may play roles by, e.g., forming tighter immune synapse [16].…”

“…The anti-CD19 moiety of AFM11 is a humanized affinity-matured version of the clone HD37 [22], the parental antibody used for the construction of blinatumomab [64], while duvortuxizumab (a DART-Fc) has humanized anti-CD19 mAb BU12 as its targeting moiety [67]. The affinities of blinatumomab, AFM11, and duvortuxizumab for human CD19 are 2.1, 0.37, and 2.0 nM, respectively.…”

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

“…82 Dual-affinity retargeting (DART) bispecifics can also bind 2 targets for improved potency, such as the CD19 × CD3 MGD011 shown to induce tumor regression in B-cell lymphoma and leukemia models. 83 Additionally, several non-oncology bispecifics are also currently in development. 84 BsAbs can be particularly useful for radionuclide delivery as part of a pretargeting strategy.…”