A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations.

Isoaspartylation appears to trigger small cell lung cancer-associated autoimmunity against neuronal protein ELAVL4.

Autoantibodies against SCLC-associated neuronal antigen ELAVL4 (HuD) have been linked to smaller tumors and improved survival, but the antigenic epitope and mechanism of autoimmunity have never been solved. We report that recombinant human ELAVL4 protein incubated under physiological conditions acquires isoaspartylation, a type of immunogenic protein damage. Specifically, the N-terminal region of ELAVL4, previously implicated in SCLC-associated autoimmunity, undergoes isoaspartylation in vitro, is recognized by sera from anti-ELAVL4 positive SCLC patients and is highly immunogenic in subcutaneously injected mice and in vitro stimulated human lymphocytes.

Myasthenia gravis with muscle specific kinase antibodies mimicking amyotrophic lateral sclerosis.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is hallmarked by the predominant involvement of bulbar muscles and muscle atrophy. This might mimic amyotrophic lateral sclerosis (ALS) presenting with bulbar weakness. We encountered four cases of MuSK MG patients with an initial misdiagnosis of ALS.

Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity.

Muscle weakness in MuSK myasthenia gravis (MG) is caused predominantly by IgG4 antibodies which block MuSK signalling and destabilize neuromuscular junctions. We determined whether the binding pattern of MuSK IgG4 antibodies change throughout the disease course ("epitope spreading"), and affect disease severity or treatment responsiveness. We mapped the MuSK epitopes of 255 longitudinal serum samples of 53 unique MuSK MG patients from three independent cohorts with ELISA.