Summary of targets and bispecific antibodies for the treatment of hematological malignancies (1)

In the past few decades, bispecific antibodies (BsAbs) have been rapidly developed for the treatment of hematological malignancies.

At present, there are more than 100 production technologies for BsAbs, and Bi-specific T cell adaptor (BiTE) is one of them.

BsAbs produced based on BiTE technology can simultaneously target CD3 and tumor-specific antigens and promote T cell cytotoxicity.

Since the first BsAb produced by BiTE technology (Blinatumomab) was approved by the U.
S.
Food and Drug Administration (FDA), research on BsAbs for the treatment of hematological malignancies has progressed rapidly.

Although BsAbs has been proved to be effective in many relapsed or refractory hematological malignancies, there are still some hematological malignancies that do not respond to BsAbs.

In order to improve the efficacy of BsAbs, the development of new BsAbs has become an upsurge in expert research.

Recently, Professor Wang Xin’s team published a review discussing the current status of BsAbs (Table 1) in the treatment of hematological malignancies.

Yimaitong organizes the main content as follows for the reference of readers.

Table 1 Bispecific antibody acute lymphoblastic leukemia for the treatment of hematological malignancies Even after high-intensity salvage chemotherapy and hematopoietic stem cell transplantation, clinical results of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) Still very poor.

New targeted drugs developed in recent years, such as BsAbs, have brought hope to the treatment of ALL.

As CD19 is overexpressed in ALL cells, BsAbs targeting CD19 and CD3, such as belintolumab and AFM11, have become a hot spot in ALL research in recent years.

01Belintuomab is a BsAb that targets CD19 and CD3.
It has been approved by the FDA for the treatment of R/R Philadelphia chromosome negative (Ph-) B-ALL, R/R Philadelphia chromosome Positive (Ph+) B-ALL and minimal residual disease (MRD) positive B-ALL patients.

Studies have also proven that belintoomab is an effective drug for the treatment of non-Hodgkin's lymphoma (NHL).

What is the specific efficacy of Nabelintouximab? How to administer it? The efficacy of belintoux (1) the treatment of R/R Ph-B-ALL Phase II study showed that after two cycles of belintoux treatment, 43% of patients with R/R Ph-ALL Achieve complete remission (CR) or complete remission with partial hematological improvement (CRh).

Among patients who relapsed after allogeneic hematopoietic stem cell transplantation, the CR/CRh rate of the patients after two cycles of belintolumab treatment was 45%.

These data confirm that belintoomab has a significant effect in aggressive ALL.

In addition, administering belintoomab before allogeneic hematopoietic stem cell transplantation can increase the CR rate, which indicates that belintoomab may be a "bridge" connecting allogeneic hematopoietic stem cell transplantation.

(2) Treatment of Ph+ ALL Since the emergence of tyrosine kinase inhibitors represented by imatinib, the prognosis of Ph+ ALL patients has been greatly improved.

However, patients with R/R Ph+ ALL who are resistant to imatinib still lack effective treatment methods, and belintoomab is a feasible solution to this problem.

Compared with chemotherapy, belintoomab can increase the CR/CRh rate of patients and improve overall survival (OS).

In a phase II study, in patients with Ph+ ALL who were intolerant or refractory to imatinib, 36% of the patients achieved CR/CRh after receiving two cycles of belintoux monotherapy.

(3) Treatment of NHL A series of clinical trials evaluating the efficacy of belintoux on NHL showed that belintoux is effective in R/R diffuse large B-cell lymphoma (DLBCL) patients and R/R NHL patients.
effective. In a phase I study of patients with R/R NHL, the maximum tolerated dose (MTD) of belintolumab was 60μg/m2/d, and the overall response rate (ORR) of patients treated with MTD was 69% .

In another phase II study, patients with R/R DLBCL who received 112 μg of belintolumab per day had ORR and CR rates of 43% and 19%, respectively.

Dosing regimen Belintolumab has a low molecular weight and a short half-life.
It is usually maintained by continuous intravenous infusion to maintain the therapeutic concentration.

The best dosing regimen for belintoomab is: in the first week of the first cycle, the dose is 9μg/d, and then the dose is increased to 28μg/d in the next 3 weeks, and then rest 2 week.

In the next cycle, the dose was 28 μg/d for 4 consecutive weeks with 2 weeks of rest.

6 weeks is a treatment cycle.

Adverse events In a phase II study of patients with R/R B-ALL, common adverse events during belintoomab treatment included fever, fatigue, headache, tremor, and leukopenia.

Most adverse events occurred in the first cycle of dosing.

In a study of adult Ph-R/R ALL patients in South Korea, the most common side effects included infections, neurological adverse events, and cytokine release syndrome (CRS).

In another trial of patients with Ph+ ALL, the most common grade 3 and above adverse events included neutropenia, thrombocytopenia, and anemia.

Research reports on patients with advanced ALL showed that the incidence of serious adverse reactions in the belintouximab group was lower than that in the chemotherapy group.

Compared with CAR-T treatment, belintolumab has a lower incidence of CRS.

The main reasons for discontinuing belintougumab treatment are serious CRS and neurological adverse events.

Severe CRS can be prevented by stepwise administration of preventive dexamethasone.

After discontinuing belintoomab, neurological symptoms can be controlled, and serious neurological events can be prevented by pre-administering steroids and close clinical monitoring.

02AFM11AFM11 is developed based on the tetravalent bispecific antibody (TandAb) technology.
It has a longer half-life and better affinity for CD3 and CD19.

In vitro experiments have shown that AFM11 can activate T cells and promote the apoptosis of leukemia cells in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma.

However, its cytotoxicity is stronger than that of belintolumab.

A phase I trial evaluated the efficacy of AFM11 in patients with R/R B-ALL.
However, the study of AFM11 was discontinued after a death caused by a neurological adverse event.

Acute Myeloid Leukemia Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults, and its incidence increases with age.

Treatment based on cytarabine and anthracyclines can cure approximately 40%-45% of young patients and 10%-20% of elderly patients.

However, the cure rate for R/R AML patients is less than 10%.

Immunotherapy has completely changed the field of AML treatment.

Currently, a large number of studies on BsAbs for the treatment of AML are in clinical trials.

Many tumor surface antigens are potential targets of BsAbs, such as CD123, CD33, FLT3, CLEC12A and WT1.

01CD123/CD3CD123 is overexpressed in many hematological malignancies, mainly in CD34+/CD38- AML cells, and CD123 overexpression means that the patient's prognosis is poor.

At present, clinical trials of several CD123/CD3 BsAbs (such as MGD006, XmAb14045 and JNJ-63709178) for the treatment of AML are in progress.

The preliminary results of clinical trials on MGD006 and XmAb14045 have been published.

MGD006MGD006 is a CD123/CD3 BsAb using dual-afnity retargeting antibody (DART) platform.

Compared with BsAbs produced by BiTE technology, it has better stability.

And its safety and effectiveness in AML patients have been proven in phase I/II clinical trials.

In the phase II study, patients with induction therapy failure/early recurrence were administered at a dose of 500 ng/kg/d, the CR/CRh rate was 26.
7%, and the total effective rate (CR/CRh/complete remission with incomplete recovery of blood cell count [ CRi]) is 30.
0%.

The median OS of patients who achieved CR/CRh was 10.
2 months, and the 6-month and 12-month survival rates were 75% and 50%, respectively.

The half-life of MGD006 is very short, so continuous infusion is required.

Like other BsAbs, the most common adverse reaction of MGD006 is CRS.

The trial is still in progress, mainly for AML patients who have failed induction therapy/early relapse.

XmAb14045 (Vibecotamab) XmAb14045 is a CD123/CD3 BsAb produced by XmAb technology.
It has a prolonged half-life and can be used intermittently.

XmAb14045 has been studied in phase I clinical trials.

In Part A of the study, 23% of the 64 R/R AML patients obtained CR through XmAb14045 monotherapy.

CRS was present in 77% of R/R AML patients treated with XmAb1404.

Part B of the clinical trial is studying the best dosing regimen.

02CD33/CD3CD33 is selectively expressed on AML cells.

According to reports, in 319 AML patients, the expression rate of CD33 is 87.
8%, so CD33 may be an ideal therapeutic target for AML. BsAbs targeting CD33/CD3, including AMG330 (NCT02520427), AMG673 (NCT03224819), AMV564 (NCT03144245) and GEM333 (NCTT03516760), are currently in clinical trials.

Among the above drugs, AMV564 contains two CD3 binding sites and two CD33 binding sites.

This structure not only improves its binding affinity to target cells, but also increases its molecular weight, so AMV564 has a long half-life.

In the ongoing phase I trial, patients with R/R AML received intravenous injection of AMV564 for 14 days, which is well tolerated and safe.

03FLT3/CD3FLT3 (Fms-like tyrosine kinase, FMS-like tyrosine kinase 3) belongs to the type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, its abnormal expression is related to AML and other malignant tumors The occurrence is closely related.

FLT3 is overexpressed in more than 70% of AML cases, so FTL3 is an effective target for AML treatment.

7370 is a BsAbs targeting FLT3/CD3 with long half-life and high affinity, which can effectively activate human T cells to resist FLT3+ AML cells in vivo.

The current study of 7370 is in the preclinical stage.

04CLEC12A/CD3CLEC12A is overexpressed in 90%-95% of new or recurrent AML cases, but it is rare in normal tissues.

Therefore, CLEC12A is a potential target for the treatment of AML.

Full-length human bispecific IgG-MCLA-117, can specifically bind CLEC12A+ AML cells and CD3+ T cells.

Because of its strong selectivity and does not affect the potential of normal hematopoietic stem cells, it has the ability to restore normal hematopoietic function.

A phase I clinical study of MCLA-117 (NCT03038230) is currently underway to evaluate the efficacy and safety of MCLA-117 in adult AML patients.

05WT1/CD3WT1 is a tumor-associated antigen located on chromosome 11p13, which plays an important role in controlling cell growth and differentiation.

WT1 is overexpressed in leukemia and many solid tumors, especially in AML.

Therefore, WT1 is an ideal target for the treatment of AML.

At present, drug research targeting WT1/CD3 is in the preclinical research stage.

Multiple myeloma Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells.

In recent years, new drugs have progressed rapidly, and the average overall survival of MM patients has increased to 5 years.

Although the survival rate of patients has improved, there is still no cure, and almost all MM patients eventually relapse.

In recent years, many BsAbs for the treatment of MM have been developed.
Ideal targets include BCMA, GPRC5D, CD38 and FCRL5.

01BCMA/CD3BCMA is a tumor necrosis factor receptor, specifically expressed on MM cells, and is an ideal target for the treatment of MM.

BsAbs targeting BCMA have been studied in clinical trials, and preliminary results are encouraging.

AMG 420 AMG 420 is a BsAb that targets BCMA and CD3.

A dose escalation trial to evaluate the efficacy and safety of AMG420 in R/R MM patients showed that patients cannot tolerate 800 µg/d AMG420, but a dose of 400 µg/d is appropriate.

At a dose of 400 µg/d, the remission rate and CR rate reached 70% and 50%, respectively.

In this trial, the adverse effects of AMG 420 were acceptable.

38% of 42 R/R MM patients had CRS, and 1 of them reached grade 3.

No serious central nervous system adverse events were observed.

Common serious adverse events include infection and polyneuropathy.

AMG 701 AMG 420 requires continuous intravenous infusion to maintain blood concentration, which limits the application of AMG 420, and AMG 701 happens to be a BCMA/CD3 BsAb with a longer half-life.

The efficacy of AMG 701 has been verified in vitro and animal experiments.

A phase I clinical trial of its efficacy in R/R MM patients is underway.

02GPRC5D/CD3GPRC5D is a transmembrane protein specifically expressed by MM cells, and is a poor prognostic factor for MM patients.

It can be firmly fixed on the membrane, and T cells can also bind more tightly to tumor cells, thereby promoting the cytotoxicity of BsAbs.

GPRC5D is expected to become a target for the treatment of MM, and GPRC5D/CD3 BsAbs are under development.

Talquetamab, also known as GPRC5D T cell redirection antibody, can recruit T cells to tumor cells and activate T cells.

The drug showed anti-tumor activity in a xenograft mouse model.

However, there is currently a lack of safety information for the drug.

A clinical trial investigating the safety and recommended dose of talentamab in R/R MM patients is ongoing (NCT03399799).

03CD38/CD3CD38 is a transmembrane protein that is selectively expressed on MM cells.

This molecule can be used to distinguish MM cells from normal cells.

Researchers have developed several anti-CD38/CD3 BsAbs, including AMG 424 and Bi38-3.

AMG 424 can effectively kill target cells without causing severe CRS, and is expected to play a role in patients who relapse after daratumumab treatment.

Although T cells expressing CD38 may be attacked by AMG 424, this side effect is acceptable.

Another BsAb Bi38-3 that targets CD38/CD3 has also shown efficacy in mouse models.

Compared with AMG 424, Bi38-3 has less adverse effects on normal cells.

04FCRL5/CD3 BsAbs targeting FcRH5/CD3 can recruit T cells to attack plasma cells and MM cells.

The anti-FcRH5/CD3 T cell dependent bispecific antibody (TDB) developed based on KiH technology can effectively attack FCRL5+ MM cells.

In mouse models and cynomolgus monkey models, anti-FcRH5/CD3 TDB can limit the growth of xenograft MM cells.

Combined with PD-1/PD-L1 inhibitors can improve the efficacy of anti-FcRH5/CD3 TDB.

Anti-FcRH5/CD3 TDB has a longer half-life and should be administered intermittently.

······The next issue will continue to introduce the targets and bispecific antibodies for the treatment of "Non-Hodgkin's Lymphoma", "Hodgkin's Lymphoma" and "Myelodysplastic Syndrome".
Welcome everyone to continue to pay attention.
.

Reference materials: Tian Z, Liu M, Zhang Y, Wang X.
Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies.
J Hematol Oncol.
2021 May 3;14(1):75.
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