Impact of carbamylation on IgG mediated complement activation

Transplantation and autoimmunit

An AXL-specific antibody-drug conjugate shows preclinical anti-tumor activity in non-small cell lung cancer, including EGFR-inhibitor resistant NSCLC

Transplantation and autoimmunit

Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity

Background Immunosuppressive extracellular adenosine is generated by the enzymatic activity of CD73. In preclinical models, antibodies (Abs) targeting different epitopes on CD73 exert anticancer activity through distinct mechanisms such as inhibition of enzymatic activity, engagement of Fc receptors, and spatial redistribution of CD73. Methods Using controlled Fab arm exchange, we generated biparatopic bispecific antibodies (bsAbs) from parental anti-CD73 Abs with distinct anticancer activities. The resulting anticancer activity was evaluated using in vitro and in vivo models. Results We demonstrate that different anticancer activities can be combined in a biparatopic bsAb. Remarkably, the bsAb significantly improved the enzyme inhibitory activity compared with the parental Abs, which led to neutralization of adenosine-mediated T-cell suppression as demonstrated by proliferation and interferon gamma (IFN-gamma) production and prolonged survival of tumor-bearing mice. Additionally, the bsAb caused more efficient internalization of cell surface CD73 and stimulated potent Fc-mediated engagement of human immune effector cells in vitro and in vivo. Conclusions Our data collectively demonstrate that complementary anticancer mechanisms of action of distinct anti-CD73 Abs can be combined and enhanced in a biparatopic bsAb. The multiple mechanisms of action and superior activity compared with the monospecific parental Abs make the bsAb a promising candidate for therapeutic targeting of CD73 in cancer. This concept may greatly improve future Ab design

Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas

Despite the rapid and widespread integration of chimeric CD20 monoclonal antibody (mAb), rituximab, into the management of non-Hodgkin lymphoma, its efficacy remains variable and often modest when used as a single agent. To develop more potent reagents, human immunoglobulin transgenic mice were used to generate a panel of immunoglobulin G1kappa (IgG1kappa) CD20 mAbs. All reagents bound strongly to CD20(+) cells and recruited mononuclear cells for the lysis of malignant B cells. However, 2 mAbs, 2F2 and 7D8, were exceptionally active in complement-dependent cytotoxicity (CDC), being able to lyse a range of rituximab-resistant targets, such as CD20-low chronic lymphocytic leukemia (CLL), in the presence of human plasma or unfractionated blood. Further analysis showed that 2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100-insoluble regions of the plasma membrane, but that they had markedly slower off-rates. To determine whether off-rate influenced CDC, a non-complement activating F(ab')(2) antihuman kappa reagent was used. This reagent markedly slowed the off-rate of rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity

Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma

Transplantation and autoimmunit