Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.This work was supported by a Sir Henry Dale Fellowship (J.R.J.) jointly funded by the Wellcome Trust and the Royal Society (grant number: 099966/Z/12/Z). PhD studentships (S.A.M. and M.J.H.) were funded by the Wellcome Trust (grant number: 102195/Z/13/Z)

Effects for Efficiency: Asymptotic Speedup with First-Class Control

We study the fundamental efficiency of delimited control. Specifically, we show that effect handlers enable an asymptotic improvement in runtime complexity for a certain class of functions. We consider the generic count problem using a pure PCF-like base language $\lambda_b$ and its extension with effect handlers $\lambda_h$. We show that $\lambda_h$ admits an asymptotically more efficient implementation of generic count than any $\lambda_b$ implementation. We also show that this efficiency gap remains when $\lambda_b$ is extended with mutable state. To our knowledge this result is the first of its kind for control operators