Hillstream BioPharma, Inc. announced the development of proprietary targeted biologics, Knob Quatrabodies™ (HSB-1940) against PD-1. Hillstream signed separate collaboration agreements with a subsidiary of OmniAb, Inc. and with Minotaur Therapeutics, Inc. to advance Picobodies against novel, unreachable and undruggable epitopes in high-value validated targets starting with PD-1. The technologies of Hillstream and Minotaur will be combined under a previously disclosed license from OmniAb to discover, develop and advance biotherapeutics against high-value validated targets. Picobodies are antibody “knob” domains comprised of cysteine-rich ultralong complementary determining region (CDR) H3 sequences of 30-40 amino acids, which have the potential to access challenging epitopes better than full size antibodies can. By combining Quatramers with their long half-life coated with a PD-1 Picobody™ to create HSB-1940, Hillstream believes it could more efficiently target novel epitopes with greater binding affinity than approved biologics.

Targeting PD-1 is a step toward enabling Hillstream to enter the rapidly growing Immuno-oncology (IO) therapeutics market with additional IO targets after PD-L1. Antibodies derived from mouse or human sources use the surface formed by complementarity determining regions (CDRs) on the variable regions of the heavy chain/light chain heterodimer, which typically forms a relatively flat binding surface. Alternative species, particularly camelids and bovines, provide a paradigm for antigen recognition through novel domains which form the antigen binding site.

However, for camelids, heavy chain antibodies bind antigen with only a single heavy chain variable region, in the absence of light chains. Meanwhile, in bovines, ultralong CDR-H3 regions form an independently folding mini-domain, which protrudes far out from the surface of the antibody and forms a “stalk and knob” structure which is diverse in both its sequence and disulfide patterns. The “knob” (Picobody) component can be expressed as an independent antigen binding domain.

At ~4-6 kDa, these are three times smaller than a camelid “nanobody”, and are the smallest known antibody fragment. These atypical antigen binding sites of bovines potentially provide the ability to interact with different antigenic determinants, particularly recessed or concave surfaces, compared to traditional antibodies.