Concepts for agonistic targeting of CD40 in immuno-oncology

Figures & data

Figure 1. Requirements for TNF-R-SF signaling.

TNF-R-SF signaling is a structurally well-defined event that requires proper three-dimensional receptor clustering and trimerization. A. The TNF-SF ligands naturally exist as trivalent functional units and the receptors are usually separated on the cell surface. B. The assembled TNF-SF ligands contain three receptor-binding sites that are located at the three identical clefts between the neighboring monomers. C. Receptor assembly into functional trimeric signaling complexes occurs through binding of the natural ligand unit. D. The interaction of these trimeric TNF-SF ligands with their corresponding receptors, expressed on the surface of other cells, leads to very precise receptor clustering followed by intracellular signal transduction.

Table 1. Antibody-based CD40-targeting compounds in ongoing clinical trials.

Therapy	Interventions	Phases	Enrollment	NCT Number	Status
ABBV-927	Monotherapy and with anti-PD1	Phase 1	198	NCT02988960	Recruiting
	Monotherapy	Phase 1	52	NCT03818542	Not yet recruiting
ADC-1013 (JNJ-64457107)	Monotherapy	Phase 1	114	NCT02829099	Recruiting
APX005M	Monotherapy	Phase 1	43	NCT02482168	Active, not recruiting
	With Pembrolizumab	Phase 1 Phase 2	41	NCT02706353	Recruiting
	With Nivolumab	Phase 1 Phase 2	100	NCT03123783	Recruiting
	With Radiation + Chemo	Phase 2	16	NCT03165994	Recruiting
	With Chemo ±Nivolumab	Phase 1 Phase 2	105	NCT03214250	Recruiting
	Monotherapy	Phase 1	45	NCT03389802	Recruiting
	With Cabiralizumab ± Nivolumab	Phase 1	120	NCT03502330	Recruiting
	With Nivolumab±Vaccine	Phase 1	40	NCT03597282	Recruiting
	With Doxorubicin	Phase 2	27	NCT03719430	Not yet recruiting
CDX-1140	Monotherapy and with Flt3L	Phase 1	180	NCT03329950	Recruiting
Chi Lob 7/4	With vaccine	Phase 1 Phase 2	44	NCT03418480	Recruiting
SEA-CD40	Monotherapy and with Pembrolizumab	Phase 1	95	NCT02376699	Active, not recruiting
Selicrelumab (RO7009789, RG7876, CP-870,893*)	With Tremelimumab*	Phase 1	32	NCT01103635	Active, not recruiting
	With Atezolizumab	Phase 1	230	NCT02304393	Recruiting
	With Chemo	Phase 1	10	NCT02588443	Recruiting
	With Vanucizumab or Bevacizumab	Phase 1	170	NCT02665416	Recruiting
	With Chemo + Atezolizumab ±Bevacizumab	Phase 1 Phase 2	205	NCT03193190	Recruiting
	With Atezolizumab + Bevacizumab	Phase 1 Phase 2	310	NCT03424005	Recruiting
	With Atezolizumab + Bevacizumab	Phase 1 Phase 2	160	NCT03555149	Recruiting

Table 2. Gene therapy and recombinant CD40 agonists in ongoing clinical trials.

Therapy	Interventions	Phases	Enrollment	NCT Number	Status
Gene therapy
GM.CD40L	Monotherapy	Phase 1 Phase 2	73	NCT01433172	Active, not recruiting
CD40L	Monotherapy	Phase 1	15	NCT03110445	Not yet recruiting
CD40L	Monotherapy	Phase 1 Phase 2	50	NCT03225989	Recruiting
Recombinant Proteins
MEDI5083	Monotherapy and with Durvalumab	Phase 1	204	NCT03089645	Recruiting

Figure 2. Side effects of CD40 agonistic antibodies versus fusion molecules.

The orientation of the target epitope of CD40 agonistic antibodies within the CD40 molecule defines epitope-driven effects. In case the antibody prevents binding of the natural CD40L it inevitably inhibits favorable natural CD40 signaling. Contrarily, cross-linking receptor complexes that have been trimerized by the natural ligand can lead to hyper-clustering and uncontrolled overstimulation with increased risk of toxic side effects and exhaustion of immune cells. Fc-domain driven effects derive from the interaction of the antibody´s Fc domain with Fc receptors on different immune cells leading to unwanted (back-)signaling. Upon Fc receptor engagement these immune cells exert diverse effector functions such as ADCC thereby not only depleting the target cell population but also contributing to unspecific immune system activation. In contrast, agonistic fusion proteins with a hexavalent/Fc-silent structure preclude the aforementioned characteristics, possibly generating a more physiologic activity.