2. Academic Validation
  3. In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor

In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor

  • Nat Biomed Eng. 2024 Dec;8(12):1715-1729. doi: 10.1038/s41551-024-01289-1.
Andi Pan 1 2 3 4,  Charles C Bailey 2,  Tianling Ou 2 3 4,  Jinge Xu 2 3 4,  Tonia Aristotelous 5,  Xin Liu 2 3 4,  Baodan Hu 2,  Gogce Crynen 6,  Nickolas Skamangas 3 4,  Naomi Bronkema 1 2 3 4,  Mai H Tran 3 4,  Huihui Mou 3 4,  Xia Zhang 7,  Michael D Alpert 8,  Yiming Yin 3 4,  Michael Farzan 9 10 11 12,  Wenhui He 13 14 15 16
Affiliations

Affiliations

  • 1 Skaggs Graduate School, Scripps Research, La Jolla, CA, USA.
  • 2 The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 3 Division of Infectious Disease, Boston Children's Hospital, Boston, MA, USA.
  • 4 Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • 5 Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA.
  • 7 The Scripps Research Institute, Jupiter, FL, USA.
  • 8 Emmune Inc., Cambridge, MA, USA.
  • 9 Skaggs Graduate School, Scripps Research, La Jolla, CA, USA. michael.farzan@childrens.harvard.edu.
  • 10 The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. michael.farzan@childrens.harvard.edu.
  • 11 Division of Infectious Disease, Boston Children's Hospital, Boston, MA, USA. michael.farzan@childrens.harvard.edu.
  • 12 Department of Pediatrics, Harvard Medical School, Boston, MA, USA. michael.farzan@childrens.harvard.edu.
  • 13 The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. hewenhui@cimrbj.ac.cn.
  • 14 Division of Infectious Disease, Boston Children's Hospital, Boston, MA, USA. hewenhui@cimrbj.ac.cn.
  • 15 Department of Pediatrics, Harvard Medical School, Boston, MA, USA. hewenhui@cimrbj.ac.cn.
  • 16 Institute for Molecular and Cellular Therapy, Chinese Institutes for Medical Research, and School of Basic Medical Sciences, Capital Medical University, Beijing, China. hewenhui@cimrbj.ac.cn.
PMID: 39638875 DOI: 10.1038/s41551-024-01289-1
Abstract

Human proteins repurposed as biologics for clinical use have been engineered through in vitro techniques that improve the affinity of the biologics for their ligands. However, the techniques do not select against properties, such as protease sensitivity or self-reactivity, that impair the biologics' clinical efficacy. Here we show that the B-cell receptors of primary murine B cells can be engineered to affinity mature in vivo the human CD4 domains of the HIV-1-entry inhibitor CD4 immunoadhesin (CD4-Ig). Specifically, we introduced genes encoding the CD4 domains 1 and 2 (D1D2) of a half-life-enhanced form of CD4-Ig (CD4-Ig-v0) into the heavy-chain loci of murine B cells and adoptively transferred these cells into wild-type mice. After immunization, the B cells proliferated, class switched, affinity matured and produced D1D2-presenting Antibodies. Somatic hypermutations in the D1D2-encoding region of the engrafted cells improved the binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein and the inhibitor's ability to neutralize a panel of HIV-1 isolates without impairing its pharmacokinetic properties. In vivo affinity maturation of non-antibody protein biologics may guide the development of more effective therapeutics.

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