Why is Pfizer's US$2.26 billion "Don't Eat Me" signal channel favored by many major pharmaceutical companies?

Today, Pfizer and Trillium Therapeutics jointly announced that the two parties have reached an agreement.

"Don't Eat Me" Signal Pathway-Immune Checkpoints of Macrophages

When it comes to immune checkpoint proteins, we may all think of the classic signaling pathway PD-L1/PD-1

However, many tumor cells express CD47 to help them escape macrophages

▲The CD47-SIRPα signaling pathway is an important signaling pathway for tumors to evade the innate immune system (picture source: reference [2])

However, drug development in this field needs to face two important challenges: one is that blocking the "don't eat me" signaling pathway alone is not enough to destroy tumor cells; the other is because CD47 is expressed in all cells, so it is blocked.

Activate macrophages while avoiding binding to red blood cells

TTI-622 and TTI-621 developed by Trillium are two innovative CD47 blocking therapies

▲TTI-622 and TTI-621 provide the "eat me" signal while blocking the "don't eat me" signal (picture source: reference [6])

At the same time, these two fusion protein therapies hardly bind to normal red blood cells, thereby reducing the risk of anemia caused by blocking CD47, and because they will not be captured by red blood cells before binding to tumor cells, TTI- 622 and TTI-621 may only require lower doses to achieve therapeutic effects

▲TTI-622 and TTI-621 hardly bind to red blood cells, reducing the risk of side effects (picture source: reference [2])

In a phase 1 clinical trial for the treatment of patients with relapsed/refractory lymphoma, TI-622 as a single-agent treatment showed good safety and achieved an objective response rate (ORR) of 33%, including 2 patients who achieved complete Remission, one of which lasted for more than 114 weeks

A variety of CD47 targeted therapies enter the clinical development stage

At present, many biomedical companies are developing different types of CD47 targeted therapies.

▲Some CD47-SIRPα signaling pathway targeted therapies that are in clinical development (data source: public information, drawing by WuXi AppTec's content team, click for larger image)

A variety of research and development strategies can be seen in reducing the side effects of blocking the CD47-SIRPα signaling pathway

In addition, some companies have adopted methods of removing or inactivating the Fc protein domain to reduce the side effects of therapies (such as ALX Oncology's evorpacept and Kahr Medical's DSP107)

In terms of enhancing the anti-cancer ability of therapies, many companies have adopted the strategy of bispecific molecules.

Reference materials:

[1] PFIZER TO ACQUIRE TRILLIUM THERAPEUTICS INC.

[3] Yang et al.

[4] Oronsky et al.

[5] Trillium gets a buyout while it's down.