Preclinical Efficacy of IMM-BCP-01, a Highly Active Patient-Derived Anti-SARS-CoV-2 Antibody Cocktail

Using an unbiased interrogation of the memory B cell repertoire of convalescent COVID-19 patients, we identified human antibodies that demonstrated robust antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants. Here, we describe the pre-clinical characterization of an antibody cocktail, IMM-BCP-01, that consists of three unique, patient-derived recombinant neutralizing antibodies directed at non-overlapping surfaces on the SARS-CoV-2 spike protein. Two antibodies, IMM20184 and IMM20190 directly block spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its unique epitope on the outer surface of RBD, alters the conformation of the spike trimer, promoting release of spike monomers. These antibodies decreased SARS-CoV-2 infection in the lungs of Syrian golden hamsters, and efficacy in vivo efficacy was associated with broad antiviral neutralizing activity against multiple SARS-CoV-2 variants and robust antiviral effector function response, including phagocytosis, ADCC, and complement pathway activation. Our pre-clinical data demonstrate that the three antibody cocktail IMM-BCP-01 shows promising potential for preventing or treating SARS-CoV-2 infection in susceptible individuals. One sentence summaryIMM-BCP-01 cocktail triggers Spike Trimer dissociation, neutralizes all tested variants in vitro, activates a robust effector response and dose-dependently inhibits virus in vivo.

Unbiased interrogation of memory B cells from convalescent COVID-19 patients reveals a broad antiviral humoral response targeting SARS-CoV-2 antigens beyond the spike protein

Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.

Strengthening of human quadriceps muscles by cutaneous electrical stimulation.

The effectiveness of cutaneous electrical stimulation as a muscle-strengthening technique was evaluated by comparison with an isometric regime. Sixteen normal healthy subjects were randomly assigned to either an electrical group or an isometric group. A pretest was given of maximum voluntary force in the quadriceps (extensor) muscles, measured with a cable tensiometer. Subjects then trained (isometrically or by electrical stimulation) four days per week for three weeks. Training by electrical stimulation was via a square-wave pulse (75 Hz and 0.1 ms) with the voltage determined by subject tolerance for ten, 10-sec induced contractions (with 50-sec rest intervals). Isometric training consisted of ten, 10-sec maximal contractions (with 50-sec rest intervals) at each session. Feedback of the generated force was standardised for both groups. Post-training measures were then administered using the same protocol as the pretest. Both groups demonstrated a marked improvement in quadriceps strength of 22 +/- 5.3% for the electrical group and 25 +/- 6.9% increase for the isometric group (p less than 0.02). The change in strength was apparently not dependent on the magnitude of the stimulating voltage (5-10 V) nor on the tension induced. There was no significant difference in the strength gains achieved by the two regimes (p greater than 0.05). No pain, muscle lesions or other ill effects were observed with electrical stimulation. We conclude that cutaneous electrical stimulation is a viable strengthening technique. There are obvious practical applications of this technique to the rehabilitation of patients who are not able to maintain an effective voluntary contraction.