Recent months have seen surges of SARS-CoV-2 infection across the globe along with considerable viral evolution. Extensive mutations in the spike protein may threaten efficacy of vaccines and therapeutic monoclonal antibodies. Two signature mutations of concern are E484K, which plays a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here, we report the emergence of a novel variant lineage B.1.526 that contains E484K and its alarming rise to dominance in New York City in recent months. This variant is partially or completely resistant to two therapeutic monoclonal antibodies in clinical use. It is also less susceptible to neutralization by convalescent plasma or vaccinee sera by 4.1-fold or 3.3-3.6-fold, respectively. The B.1.526 lineage has now been reported from at least 32 states in the US and numerous other countries. B.1526 has been outpacing B.1.1.7 in Northern Manhattan, and both variants have been spreading throughout New York with comparable estimated doubling times. Such transmission dynamics, together with its resistance to therapeutic antibodies, would warrant B.1.526 as a SARS-CoV-2 variant of concern.