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7:02 PM
 | 
Aug 09, 2019
 |  BioCentury  |  Product Development

Eat this, don’t eat that: CD47 companies’ first hurdle

The race in CD47 is now about teaching macrophages to eat tumor cells and not healthy ones

The rush to drug CD47 shows no signs of abating, with five companies launching clinical programs for cancer this year and three moving forward on the back of encouraging Phase I data. The differentiator may be in which company develops the cleverest strategy to tell macrophages which cells to eat and which to leave alone.

Having briefly occupied the limelight as the next PD-1, CD47 is moving to the harsh light of day as companies work out how to capitalize on its broad potential in cancer, without falling foul of the safety issues that have already downgraded at least one candidate.

Interest in the target was kicked off by findings from Irv Weissman’s lab at Stanford University, which demonstrated anti-tumor effects of blocking CD47, a “don’t eat me” signal that prevents cells from being engulfed by macrophages. The idea is that preventing the interaction between CD47 on tumor cells and SIRPA, its binding partner on macrophages, would relieve a blockade on innate antitumor immunity, similar to the way PD-1 inhibitors release the brakes on antitumor T cells (see “Forty Seven and Counting”).

Weissman co-founded Forty Seven Inc. in 2015. Since then, at least 11 other companies have announced CD47 programs, and at least 24 compounds are in development targeting CD47 or SIRPA, according to BioCentury’s BCIQ database.

Weissman, a professor of pathology and developmental biology, is also director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford.

“All more or less looked similar from a preclinical perspective. You moved them into the clinic, and they all look very different.”

Jeff Goater, Surface Oncology

However, early clinical studies, in particular by Surface Oncology Inc., have revealed dose-limiting hematological toxicity to be a sticking point for the target.

Surface saw two neutropenia-related dose-limiting toxicities at a lower than expected dose in an all-comer Phase I trial of its anti-CD47 mAb SRF231, and has deprioritized its program. Celgene Corp. terminated a Phase I trial of its anti-CD47 mAb CC-90002 in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), but has not disclosed data. A separate Phase I trial in combination with Rituxan rituximab to treat hematologic neoplasms is ongoing.

Other companies have also reported toxicity due to excessive elimination of red blood cells (RBCs), platelets or neutrophils.

The problem is that because CD47 is ubiquitously expressed, healthy cells act as antigen sinks that soak up anti-CD47 mAbs, which means high doses are needed to target tumors. But those high doses also suppress the “don’t eat me signal” on blood cells, prompting macrophages to engulf them and causing hematological toxicity.

According to Surface CEO Jeff Goater, animals haven’t been a viable testing ground to tease out differences in toxicity.

“You have a set of antibodies all more or less looked similar from a preclinical perspective. You moved them into the clinic, and they all look very different,” said Goater.

Forty Seven, Trillium Therapeutics Inc. and ALX Oncology Ltd. have each reported clinical data they see as proof-of-concept for their compounds (see Table: “CD47’s Clinical Report Card”). The next two years should see more results from the latest wave of entrants to the clinic.

All ten companies with clinical-stage compounds have disclosed strategies to solve the toxicity, with a common theme being addition of a second component that creates a tumor-specific “eat me” signal. This leverages the fact that binding to CD47 alone is not enough to induce cancer killing; it needs to be coupled with active stimulation of phagocytosis from an anti-CD47 mAb’s Fc domain or another source, either of which can be delivered separately, in a more tumor-specific fashion.

Surface has not completely abandoned its program. The company testing whether lower, more frequent dosing could reduce the neutropenia risk, and sees an opportunity for the compound in transplant conditioning.

At least three companies with clinical-stage CD47 inhibitors are also developing candidates against SIRPA, whose narrower expression profile reduces tox risk (see Sidebar: “The Eater’s Side”).


Sidebar: The eater’s side

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