Combination Strategies to Boost T Cell Bispecific Antibodies Activities
Teemu Junttila, PhD, Distinguished Scientist, Molecular Oncology, Genetech
Co-Stimulation Could Make Antibodies More Effective Against Solid Tumors
Solid tumors are proving harder to treat with immunoglobulins than blood cancers, according to a leading researcher, who says boosting T-cell bispecific antibody activity using co-stimulation may hold the key to more successful therapies.
Teemu Junttila, PhD, Distinguished Scientist, Molecular Oncology at Genentech, outlined the idea at the Antibody Engineering and Therapeutics Europe conference, telling delegates, “What is really becoming obvious is that we are not able to achieve similar success in solid tumours [to that seen in in blood cancers].
“I was able to find at least 80 antibodies in ongoing clinical trials for solid tumors. And I think what we’ve seen on the activity side is rather modest compared to the responses in haematology. The overall response has remained under 30%,” he said.
“So something clearly seems to be different or missing,” he said, adding “The targets obviously are substantially worse compared to the hematological lineage markers. Also, the number of T-cells in tumors is likely limiting antibody activity.
“Or T-cells may have problems getting to the tumors. In addition, the microenvironment can be suppressive. Furthermore, co-stimulation is likely missing. So there’s a lot of potential problems.”
Co-Stimulation
To try and address these challenges, the industry is working to boost T-cell bispecific antibody activity, Junttila said, explaining that co-stimulation is one of the main avenues of study.
He began by looking at the use of co-stimulatory receptors, citing their efficacy in enhancing the activity of CAR-T therapies as a model.
“So as we know in the absence of costimulatory domain CAR T-cells don’t really work but adding CD28 or 4-1BB makes them work really well,” Junttila said.
To further examine the role of these co-stimulatory receptors, Junttila and his colleagues made HER-targeted antibodies, one of which targeted CD28 while the other aimed at 4-1BB.
“Looking at the key differences, one thing is obvious. CD28 is consistently expressed in T-cells compared to the 4-1BB, which is absent in peripheral blood T-cells but is readily induced by TCR stimulation, in this case with the T-cell bispecific,” he said.
“Another major difference between these pathways is that 4-1BB induction happens predominantly on CD8 cells and a much lesser extent in CD4 cells, whereas the reverse is true for CD28.”
The team then examined how each co-stimulatory antibody performed in terms of the ability to activate T-cells and kill tumors, with the results indicating they function in different ways.
“Only CD28 is able to increase T-cell, but that’s most likely explained by the fact that 4-1BB is not even expressed at this point … Similarly, we see that CD28 induces a much more robust cytokine release, again, with the same caveat,” Junttila said.
“We do start seeing that 4-1BB increases T-cell bispecific mediated cytokine release. So the majority of the cytokines go up. The notable exception is IL-10, which is consistently lowered with, with 4-1BB co-stimulation.”
Junttlia said that both molecules have a highly potent effect on increasing the killing activity of T-cell bispecifics.
