Five years ago I wrote a Technical Note on Poly-sspecific antibodies. Simply stated these complex antibodies could bind to multiple surface markers on a cancer cell as well as attaching to an immune cell, thus facilitating an aggressive immunotherapeutic response targeted specifically to the cancer cell.
A recent paper in Nature Cancer, details how these PSAb have been developed and are being used in multiple myeloma. The author notes:
To create the components of the new trispecific antibody, ISB 2001, the authors selected high-affinity antibody Fab fragments (the region of an antibody that gives antigen specificity) directed against both CD38 and BCMA, two well-validated targets in the MM therapeutics landscape3,5. The two anti-tumor Fab fragments were combined into a single trispecific antibody molecule with a Fab fragment directed against the T cell activation antigen CD3. A Fab fragment with medium-low affinity for CD3 was used because this was previously shown to help improve the balance between TCE efficacy and safety6,7. The anti-CD38 Fab fragment was additionally selected to recognize an epitope distinct from that recognized by daratumumab. This was done to avoid potential dampening of the activity of ISB 2001 in patients with r/r MM who have been recently treated with a daratumumab-based regimen. In addition, Carretero-Iglesia et al.4 generated an array of monospecific and bispecific control molecules. Together, these make for exceptionally well-controlled experiments from which the reader and fellow scientists can easily draw conclusions. The CD3, CD38 and BCMA Fab fragments were combined with an antibody Fc fragment that was mutated to retain its ability to extend the antibody in vivo half-life while preventing it from interacting with IgG Fc receptors, thereby minimizing target-binding-independent T cell activation. Here, the spatial configuration of the Fab fragments was found to be crucial for optimal activity. Placing either of the tumor-targeting Fab fragments close to the CD3 Fab (meaning on the same antibody heavy chain) resulted in greater potency than did distal positioning (on the other heavy chain). In the trispecific setting, having the BCMA tumor-binding Fab positioned between the Fc fragment and the CD3 Fab was optimal for cytotoxicity (Fig. 1). As CD38 has a broader expression profile than BMCA (CD38 is more often expressed on non-tumor cells), placing the CD38 Fab in the less-active distal position resulted in reduced on-target off-tumor T cell activation, with the promise of maximizing the therapeutic window. Avidity (the combined binding strength in antibody–antigen complexes) is fundamental to antibody functional responses8. By mixing antibodies directed against multiple epitopes on a given antigen, high-avidity immune complexes may be formed that are characterized by tightened binding and increased activity toward cells expressing the antigen. In engineered antibodies, a covalent linkage between Fab fragments directed against distinct epitopes and/or distinct antigens may be used to generate bi- or multispecific antibodies with novel functions9. These ‘obligate bi- or multispecific antibodies’ may also benefit from higher activity due to avidity binding, an effect we might therefore call ‘obligate avidity’.
Namely the techniques we explored half a decade ago are making an entry into a significant malignancy with some hope of establishing a total remission.
Posts
