The heavy-chain only dimeric antibodies lack a light chain. When derived from the HCAb mice, HCAbs uniquely facilitate generation of soluble human VH domains, the minimal immunoglobulin recognition unit, and thus the construction of novel multi-functional molecules comprising either multiple VH domains or VH domain(s) coupled to other molecules, such as bi-specifics, Antibody Drug Conjugates or VH domain-derived diagnostic or therapeutic molecules. The molecules produced by the HCAb mice are soluble, secreted by cells and have affinities, diversity and physicochemical properties similar to traditional antibody molecules.

Approaches of HCAbs in Transgenic Mice

  1. Endogenous murine antibody expression eliminated
  2. Human (or other mammalian) transgenes introduced, w/o CH1
  3. Antigen challenge results in affinity matured HCAbs
  4. Recovery from B cells or plasma cells (hybridoma or direct cDNA expression cloning)


Features of HCAb


Potent HCAbs raised against a range of proteins including

  1. cytokines
  2. bacterial and
  3. viral targets
  4. receptors and ligands

HCAbs isolated via

  1. expression cloning
  2. hybridomas
  3. phage display

Consistent isolation of HCAbs with affinities in the high pM to nM range HCAb and derived Vh Profiles

  1. High affinity
  2. Soluble and stable
  3. Do not form aggregates in vitro
  4. Derived tetravalent human Ab are also soluble and do not aggregate
  5. HCAbs have PK characteristics in vivo comparable to human H2L2 antibodies


Applications of HCAb


HCAbs can be used directly as simplified alternatives to conventional antibodies. The VH domains from HCAbs can yield "second generation" antibody-like therapeutics:

  1. Bispecific antibodies
  2. Tetravalent antibodies
  3. Nanobodies or diabodies

Harbour has a broad, robust patent portfolio covering human heavy chain rodent technology and human heavy chain constructs, to include six US Patents, three European Patents and numerous other patents and pending applications around the world. These patent rights include US Patents #9,353,179, #9,346,877 and #8,921, 522, and European Patents #1776383 and #1864998. We are continually improving the platform and strengthening our IP position on H2L2 and HCAb transgenic mice.

Publications

  1. Dekker S, Toussaint W, Panayotou G, de Wit T, Visser P, Grosveld F, et al. Intracellularly Expressed Single-Domain Antibody against p15 Matrix Protein Prevents the Production of Porcine Retroviruses. J Virol. 2003;77(22):12132–9. (full text)
  2. Janssens R, Dekker S, Hendriks RW, Panayotou G, van Remoortere A, San JK, et al. Generation of heavy-chain-only antibodies in mice. Proc Natl Acad Sci U S A. 2006;103(41):15130–5. (full text)
  3. Laventie B-J, Rademaker HJ, Saleh M, de Boer E, Janssens R, Bourcier T, et al. Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins. Proc Natl Acad Sci U S A. 2011;108(39):16404–9. (full text)