Affimed Advances Innovative NK Cell Engager Platform with 100% ORR in Clinical Trials, Backed by Roche

Recently, VCBeat learned that biopharmaceutical company Affimed has received approval from the Nasdaq Stock Market Listing Qualifications Department to transfer its stock listing from the Nasdaq Global Market to the Nasdaq Capital Market. This transfer became effective at the start of trading hours on October 4, 2023, and the company’s shares will continue to trade under the ticker symbol “AFMD.”

Affimed, founded in 2000 and headquartered in Heidelberg, Germany, with an office in New York, is a biotechnology company dedicated to the discovery and development of cancer immunotherapies. The company focuses on the field of innate cell engagers (ICEs), specializing in the development of bispecific antibodies that target and activate natural killer (NK) cells.

Affimed has developed its proprietary ICE® molecules by leveraging its proprietary ROCK® (Redirected Optimized Cell Killing) platform technology. These molecules activate the innate immune system to eliminate cancer cells. Building on this foundation, the company has established three wholly owned pipelines and entered into a collaboration with Genentech to develop NK cell immunotherapies for the treatment of cancer.

In 2014, Affimed successfully completed its initial public offering (IPO). To date, the company has raised a total of $534 million across 14 financing rounds. Leveraging its robust pipeline of investigational candidates, Affimed has attracted investment from prominent institutions such as Roche, Aeris Capital AG, and the German Federal Ministry of Education and Research (BMBF).

CD16 protein is a crucial protein that enhances antibody-dependent cellular cytotoxicity (ADCC) in NK cells, and it is primarily divided into two subtypes: A and B.

CD16A (FcγRIIIA) is a transmembrane molecule with a unique cytoplasmic domain and two extracellular Ig-like domains, expressed on NK cells, mast cells, macrophages, and monocytes. Functionally, CD16A serves as a primary cytotoxic receptor that recognizes and binds to the Fc region of IgG antibodies attached to tumor-associated antigens, thereby triggering cytokine production or antibody-dependent cellular cytotoxicity (ADCC). It also mediates the maturation and activation of CD16A-expressing cells. Furthermore, CD16A regulates autocrine and paracrine immunity, influencing antigen presentation and inflammatory processes, including cytokine release and chemotactic cell migration. However, CD16A polymorphism (V158F) alters its binding affinity for IgG, leading to interindividual variations in immune responses.

CD16B (FcγRIIIB) is primarily expressed on neutrophils and mediates the exocytosis of granule proteins. Notably, it lacks intrinsic activating capability and shares 96% sequence homology with CD16A. Conventional CD16 antibodies currently available cannot distinguish between the A and B subtypes, resulting in cross-reactivity where the antibodies bind to both CD16A and CD16B. However, CD16B does not induce cytotoxicity against tumor cells and may even lead to adverse effects.

Therefore, specific targeting of CD16A is one of the core technologies for activating NK cells.

Affimed has taken the initiative in the development of bispecific antibodies targeting NK cell activation, leveraging its proprietary ROCK® bispecific antibody technology platform.

ROCK® was developed by Professor Melvyn Little of the German Cancer Research Center (DKFZ) for the design of innate immunotherapies, enabling the customized development of multispecific antibodies for specific patient populations.

The ROCK® platform enables the development of tetravalent multispecific antibodies that recruit NK cells or T cells to the tumor microenvironment and activate innate or adaptive immune responses against cancer. Furthermore, leveraging its modular design, the ROCK® platform allows for antibody engineering tailored to specific indications and microenvironments, generating high-affinity tetravalent bispecific ICE® molecules with targeted binding to CD16A.

Research conducted by Affimed has shown that the binding affinity of its ICE® molecules to CD16A can reach the sub-nanomolar level, approximately 1,000 times stronger than that of conventional antibodies.

ICE® molecules bind NK cells/macrophages to tumor cells by engaging the CD16A receptor and specific receptors on the tumor cell surface. Once brought into close proximity, NK cells are activated and initiate an immune response. Upon recognizing tumor cells, NK cells release perforin, which forms pores in the tumor cell membrane. Granzymes then enter the tumor cells through these pores, triggering apoptosis and ultimately leading to tumor cell death.

Furthermore, the ICE®-based CD16A antibody binds to a different epitope on the Fc region of IgG antibodies compared to conventional binders; therefore, it is unaffected by IgG levels or CD16A polymorphisms. Even in environments with high concentrations of IgG antibodies, it can effectively bind to CD16A and mediate potent antibody-dependent cellular cytotoxicity (ADCC).

Currently, Affimed has developed three pipeline candidates in development: AFM13, AFM24, and AFM28.

AFM13 is a tetravalent bispecific NK cell engager that targets the antibody Fc domain receptor CD16A and CD30, a receptor overexpressed in certain lymphomas. The mechanism of action of AFM13 enables high-affinity binding to CD16A on NK cells and macrophages, as well as to CD30 on lymphoma cells, thereby recruiting NK cells and macrophages to the vicinity of tumor cells and inducing their specific killing of CD30-positive tumor cells.

Multiple clinical trial data for AFM13 have demonstrated its favorable efficacy and safety profile.

In a Phase 2b clinical study evaluating AFM13 as monotherapy in patients with relapsed/refractory peripheral T-cell lymphoma, Affimed assessed its efficacy. The data showed an overall response rate (ORR) of 32.4% and a median duration of response (DOR) of 2.3 months.

When AFM13 is used in combination with umbilical cord blood-derived NK cell therapy, it can enhance NK cell-mediated ADCC.

Data presented by Affimed at the 2022 AACR Annual Meeting showed that among 24 patients with CD30-positive lymphoma who received the recommended Phase 2 dose (highest dose cohort), the objective response rate (ORR) for AFM13 in combination with umbilical cord blood-derived NK cell therapy reached 100%, and the complete response rate (CR) reached 70.8%.

The overall response rate (ORR) was 97% and the complete response (CR) rate was 63% across all dose groups. Among patients at all dose levels, with a median follow-up of 8 months (range: 1–23 months), the event-free survival (EFS) rate was 57% and the overall survival (OS) rate was 83%. No serious adverse events were observed, indicating favorable treatment tolerability and safety.

When combined with anti-PD-1 antibodies for the treatment of Hodgkin lymphoma, AFM13 demonstrated favorable efficacy. Data from its Phase 1b clinical trial showed that the combination therapy (at the highest therapeutic dose) achieved an overall response rate (ORR) of 88% and a complete response (CR) rate of 46%, with both ORR and CR rates exceeding those observed with anti-PD-1 antibody monotherapy.

Next, Affimed will continue to advance the new Phase 2 study (LuminICE-203) to evaluate the efficacy of the combination therapy of AFM13 and AlloNK® (AB-101) in treating relapsed/refractory Hodgkin lymphoma. AlloNK is a drug developed by the pharmaceutical company Artiva Biotherapeutics; it is an umbilical cord blood-derived allogeneic NK cell therapy candidate for the treatment of systemic lupus erythematosus.

AFM24 is a tetravalent bispecific ICE® molecule targeting EGFR (epidermal growth factor receptor), which recruits and activates NK cells and macrophages at the tumor site to mediate effective ADCC and ADCP (antibody-dependent cellular phagocytosis), thereby specifically killing cancer cells.

Unlike conventional antibodies, AFM24 functions independently of EGFR downstream signaling pathways and EGFR expression levels. It utilizes EGFR solely as a docking site without affecting its normal physiological functions in the human body. This means that AFM24 can be used to treat all EGFR-expressing tumors, including those that have developed resistance to immunomodulators.

AFM24 is being evaluated in three clinical studies.

AFM24-101 is a Phase 1/2a, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of AFM24 in patients with advanced EGFR-positive solid tumors. The results demonstrated NK cell activation and their migration to tumors in patients receiving AFM24 monotherapy, with disease stabilization observed in eight patients after dosing.

AFM24-102 is a Phase 1/2a clinical trial designed to evaluate the efficacy of combination therapy with AFM24 and Roche’s PD-L1 inhibitor atezolizumab in patients with advanced, refractory EGFR-positive solid tumors.

Data show that at the 160 mg dose level, the combination therapy demonstrated clinical activity in two patients: one patient with cutaneous metastasis from gastric cancer achieved a sustained partial response (PR), and one patient with pancreatic cancer achieved stable disease (SD) for 4 months. No dose-limiting toxicities were observed in the trial.

AFM24-103 is a Phase 1/2a study designed to evaluate the efficacy of AFM24 in combination with SNK01 (autologous non-genetically modified NK cells) from NKGen Biotech for the treatment of patients with advanced/metastatic EGFR-positive solid tumors. Data showed that, as of June 2023, seven patients with a median of five prior lines of therapy received combination treatment with AFM24 and SNK01; disease stabilization was observed in three patients, and no dose-limiting toxicities were reported in terms of safety.

AFM28 is an ICE® molecule that targets CD123 and CD16A on leukemia cells, for the treatment of patients with CD123-expressing hematologic malignancies, including acute myeloid leukemia (AML).

AML is a primary refractory or drug-resistant disease and one of the most aggressive and difficult-to-treat hematologic malignancies. Its incidence increases with age, and it is associated with an overall poor prognosis and high mortality rate. According to data published by the U.S. National Cancer Institute, the 5-year relative survival rate for patients with AML is only 29.5%.

Residual leukemic stem cells (LSCs) are the fundamental cause of drug resistance and relapse in acute myeloid leukemia (AML). LSCs are a subpopulation of AML cells characterized by self-renewal capacity and the ability to initiate leukemia, and they exhibit resistance to conventional anti-leukemic therapies. Therefore, it is crucial to effectively eliminate leukemic blasts and eradicate residual LSCs.

Preclinical data for AFM28 demonstrate that, in a panel of AML cell lines, AFM28 successfully engages allogeneic NK cells via ADCC, leading to the destruction of CD132-positive tumor cells. Notably, AFM28-induced ADCC is independent of the mutational profile of leukemia cells and effectively targets cells with low CD123 expression levels.

This finding was also confirmed in AML mouse models. Compared with untreated control mice, mice treated with AFM28 and NK cell therapy exhibited lysis of CD123-positive leukemic cells and controlled tumor growth.

Currently, the first-in-human Phase I clinical study of AFM28 has been initiated to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AFM28 monotherapy in patients with CD123-positive relapsed or refractory acute myeloid leukemia (r/r AML).

Leveraging robust clinical data from multiple pipeline candidates and its proprietary ROCK® platform technology, Affimed has established collaborations with biopharmaceutical companies Roivant Sciences and Genentech.

In 2020, Affimed entered into a collaboration agreement with Roivant to develop and commercialize novel ICE® molecules. Under the agreement, Roivant obtained the development license rights for Affimed’s preclinical molecule AFM32, while Affimed received a $60 million upfront payment. Currently, AFM32 remains in the preclinical development stage.

In 2018, Affimed entered into a collaboration with Genentech valued at up to $5 billion to jointly develop and commercialize immunotherapies based on NK cell engagers. To date, the two parties have not disclosed detailed information on the related pipeline.