PHE1-based IgG-like antibody platform provides a novel strategy for enhanced T-cell immunotherapy

TL;DR

This study introduces a new antibody platform called PHE-Ig that improves T-cell immunotherapy by enabling the creation of effective bispecific antibodies for cancer treatment.

Contribution

The PHE-Ig platform uses PHE1 fragment technology to enhance heavy and light chain pairing in bispecific antibodies for T-cell immunotherapy.

Findings

PHE-Ig technology successfully promotes HC-LC pairing and enables the production of functional bispecific antibodies.

BCMA×CD3 PHE-Ig bispecific antibodies showed strong anti-multiple myeloma activity in both in vitro and in vivo models.

A shortened version of PHE1 (PHE-S) also demonstrated effective anti-tumor activity, offering new possibilities for bsAb development.

Abstract

Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.

This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo.

We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity in vitro and in vivo.

Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.

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